Methods and compositions for raf kinase mediated diseases

ABSTRACT

The invention features compounds, pharmaceutical compositions and methods for treating patients who have an EGFR-driven cancer of Formula (I), wherein the variables are as defined herein.

BACKGROUND OF THE INVENTION

This invention relates to pharmaceutical compositions and methods forinhibiting the proliferation of cells.

In human clinical studies with non-small cell lung cancer (NSCLC)patients, the kinase inhibitors, erlotinib and gefitinib have been foundto be effective, but in only a subset of patients. It was laterdetermined that the responsive patients had certain mutations in thegene for epidermal growth factor receptor (EGFR). The mutant forms ofEGFR are enzymatically active without the need for ligand stimulation.They are also particularly sensitive to kinase inhibitors like erlotiniband gefitinib, which competitively bind to the ATP binding site of theEGFR kinase domain. Those mutations have been cataloged and described atlength in the scientific literature. They include small deletions orpoint mutations in the kinase domain as has previously been writtenabout extensively. See e.g., Sharma, Nat. Rev. Cancer 7:169 (2007) (exon19 mutations characterized by in-frame deletions of amino-acids 747account for 45% of mutations, exon 21 mutations resulting in L858Rsubstitutions account for 40-45% of mutations, and the remaining 10% ofmutations involve exon 18 and 20); Sordella et al., Science 305:1163(2004); and Mulloy et al., Cancer Res. 67:2325 (2007).

Unfortunately, additional mutations in the EGFR gene, e.g., the T790Mmutation, render drugs like erlotinib and gefitinib less effective.Those mutations are associated with resistance to the drugs and torelapse in patients with cancer cells having the T790M mutation.

New therapies are needed for the treatment of EGFR-driven cancers inwhich mutations confer resistance to front line tyrosine kinaseinhibitor (“TKI”) therapies. In particular, new therapies for inhibitingcells expressing such gefitinib-resistant or erlotinib-resistant EGFRgenes could be of profound benefit.

SUMMARY OF THE INVENTION

This invention relates to the discovery of a class of compounds thatinhibit EGFR and medically significant mutant forms thereof. Thosemutants include mutant EGFR proteins that are enzymatically active inthe absence of protein ligand and mutants such as the T790M EGFR mutantthat are resistant to the EGFR inhibitors erlotinib and gefitinib.Compounds of this invention possessing desirable selectivity for theintended biological targets and advantageous pharmaceutical propertiesmake them of interest for treating cancers characterized by theexpression of EGFR or an EGFR mutant, especially in cases that areresistant or refractory to erlotinib or gefitinib.

This invention provides a compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein

U¹ and U² are both N and U³ is C—R^(e); or U³ is N, one of U¹ and U² isN, and the other is C—R^(d); or U³ is C—R^(e), one of U¹ and U² is N,and the other is C—R^(d);

V¹ is O, S, NR^(V), CO, CH₂, or CF₂;

R^(V) is H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,cycloalkynyl, or aryl;

R^(d) is H, halo, CN, alkyl, cycloalkyl, alkoxy, haloalkyl, alkenyl,haloalkenyl or halocycloalkyl;

R^(e) is H or NH₂; or, R^(d) and R^(e), together with the ring atom towhich each is attached, form a 5- or 6-membered ring containing one, twoor three heteroatoms, independently selected from N, S and O, whereinthe 5- or 6-membered ring so formed is substituted with R^(h) which isC₁₋₄ alkyl or halo;

R^(g) is H, F, —P(O)(R^(3A))(R^(3B)), —S(O)N(R^(3C))(R^(3D)),—S(O)₂R^(3E), —C(O)N(R^(3F))(R^(3G)), —OC(O)N(R^(3F))(R^(3G)),—NR^(3H)C(O)OR^(3I) or a 5- or 6-membered heterocyclic ring comprising1, 2, 3 or 4 N atoms;

-   -   each R^(3A), R^(3B), R^(3C), R^(3D), R^(3E), R^(3F), R^(3G),        R^(3H), and R^(3I) is independently selected from H, alkyl,        alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, and        heteroalkyl, or R^(3A) and R^(3B), or R^(3C) and R^(3D), or        R^(3F) and R^(3G), together with the atom to which each is        attached, form an unsubstituted or substituted 5- or 6-membered        heterocyclic ring;

R^(g2) is H, F, W¹, —P(O)(R^(3A))(R^(3B)), —S(O)N(R^(3C))(R^(3D)),—S(O)₂R^(3E), —C(O)N(R^(3F))(R^(3G)), —OC(O)N(R^(3F))(R^(3G)),—NR^(3H)C(O)OR^(3I), C₁₋₆ alkoxy or C₁₋₄ alkyl;

or, R^(g2) and R^(g) together with the atom to which each is attachedform an unsubstituted or substituted 5- to 7-membered heterocyclic ringcomprising 1-3 heteroatoms independently selected from P, N, O and S;

R^(g1) is H, F, —OR², —P(O)(R^(3A))(R^(3B)), —S(O)N(R^(3C))(R^(3D)),—S(O)₂R^(3E), —C(O)N(R^(3F))(R^(3G)), —OC(O)N(R^(3F))(R^(3G)),—NR³HC(O)OR^(3I), or substituted or unsubstituted 5- or 6-memberedheterocyclic ring;

Ring A is:

R^(b2) is H, F, or an optionally substituted 5- or 6-memberedheterocyclic ring containing 1, 2 or 3 N or O atoms;

R^(b4) is H, F, W¹, C₁₋₆ alkoxy, C₃₋₆ alkenyloxy, C₃₋₆ cycloalkoxy,—OC(O)N(R^(5A))(R^(5B)), —NR^(5C)C(O)OR^(5D), or substituted orunsubstituted 5- or 6-membered heterocyclic ring comprising 1, 2 or 3 Nor O atoms;

each R^(5A), R^(5B), R^(5C) and R^(5D) is independently H, alkyl,alkenyl, alkynyl or heteroalkyl, or R^(5A) and R^(5B), together with theatom to which each is attached, form a substituted or unsubstituted 5-or 6-membered heterocyclic ring;

R^(a1) is H, halo, W¹, —CN, —NO₂, —R¹, —OR², —O—NR¹R², —NR¹R²,—NR¹—NR¹R², —NR¹—OR², —C(O)YR², —OC(O)YR², —NR¹C(O)YR², —SC(O)YR²,—NR¹C(═S)YR², —OC(═S)YR², —C(═S)YR², —YC(═NR¹)YR², —YC(═N—OR¹)YR²,—YC(═N—NR¹R²)YR², —YP(═O)(YR¹)(YR²), —S(O)_(r)R², —SO₂NR¹R²,—NR¹SO₂NR¹R² or

and X₁ and X₂ are each independently CH or N;

or R^(a1) and R^(b4), together with the atom to which each is attached,form an optionally substituted 5- or 6-membered heterocyclic ringcomprising 1, 2 or 3 heteroatoms independently selected from N and O;

R^(a2) is H, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₃₋₆ cycloalkyl, C₁₋₆alkoxy, C₂₋₆ alkenyloxy, C₃₋₆ cycloalkyloxy or 4- to 7-memberedheterocyclyl, wherein the alkyl, alkenyl, cycloalkyl, alkoxy, C₂₋₆alkenyloxy, cycloalkyloxy and heterocyclyl are unsubstituted orsubstituted with one or more halo, amino, C₁₋₆ alkylamino, or di-Cmalkylamino groups;

Y is independently a bond, —O—, —S— or —NR¹—;

R¹ and R² are independently H or R¹⁵;

R⁴ is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl,aryl, heteroalkyl, heterocyclic and heteroaryl;

W¹ is —NR⁷C(O)C(R¹¹)═CR⁹R¹⁰, —C(O)C(R¹¹)=CR⁹R¹⁰, —CH₂P(O)C(R¹¹)═CR⁹R¹⁰,—OP(O)C(R⁸)═CR⁹R¹⁰, —NR⁷S(O)₂C(R⁹)(R¹⁰)(R^(X)), —NR⁷S(O)₂C(R¹¹)═CR⁹R¹⁰,—NR⁷C(O)C≡C—R¹⁴, —NR⁷C(O)C(R⁹)(R¹⁰)(R^(X)),

R^(X) is halo;

R⁷ is H, alkyl or heteroalkyl, wherein the alkyl and heteroalkyl groupsare independently optionally substituted with an amino, alkylamino ordialkylamino group;

R⁸ is C₁₋₆ alkyl;

R⁹ and R¹⁰ are independently H, halo, —C(O)R¹⁶, alkyl, alkoxy, alkenyl,alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroalkyl,heterocyclyl or heteroaryl, wherein R⁹ and R¹⁰, if not H, are optionallysubstituted with one or more halo, amino, alkylamino, dialkylamino,alkoxy, cycloalkyl, heterocyclyl or heteroaryl groups, wherein saidgroup, if not halo, is optionally substituted with one or more halo,C₁₋₄ alkyl, alkoxyl, halo(C₁₋₄)alkyl or C₃₋₇ cycloalkyl groups;

R¹¹ is H, halo, —C(O)—OR¹², alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, cycloalkynyl, aryl, heteroalkyl, heterocyclic, orheteroaryl, wherein R¹¹, if not H, is optionally substituted with one ormore halo, amino, alkoxyl, cycloalkyl, heterocyclic or heteroarylgroups, wherein said group, if not halo, is optionally substituted withone or more halo or alkyl, alkoxyl, cycloalkyl or heterocyclyl groups,wherein the alkyl, alkoxyl, cycloalkyl and heterocyclyl group isoptionally substituted with one or more alkyl, halo or hydroxylsubstituents;

or R⁹ and R¹¹, taken together with the atom to which each is attached,form a cycloalkenyl or heterocyclic ring;

R¹² is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl,aryl, heteroalkyl, heterocyclic, or heteroaryl;

R¹³ is H or C₁₋₄ alkyl;

R¹⁴ is R^(T) or R^(W);

R¹⁵ is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl,aryl, heteroalkyl, 4- to 7-membered heterocyclyl, or heteroaryl, whereineach R¹⁵ is optionally substituted with one or more halo, cycloalkyl,heterocyclic or heteroaryl groups, wherein said cycloalkyl, heterocyclicor heteroaryl groups(s) are independently optionally substituted withone or more halo, alkyl, haloalkyl, hydroxyalkyl, amino, dialkylamino orcycloalkyl groups;

R¹⁶ is OH, —O-alkyl, cycloalkyl, heterocyclyl, —NH₂, —NH-alkyl, or—N-dialkyl wherein the alkyl, cycloalkyl or heterocyclyl moiety isoptionally substituted with halo, amino, alkylamino, dialkylamino, alkylor hydroxyl;

R^(T) is H or —CH₃;

R^(W) is halo; substituted methyl; or an optionally substituted groupselected from (C₂₋₆)alkyl, (C₁₋₆)heteroalkyl, heterocyclyl, aryl andheteroaryl; wherein the substituents on the optionally substituted(C₂₋₆)alkyl, (C₁₋₆)heteroalkyl, heterocyclyl, aryl and heteroaryl groupsare selected from halo, haloalkyl, alkoxy, heterocyclyl, substitutedheterocyclyl, amino, alkylamino, and dialkylamino, and in the case of anoptionally substituted heterocyclyl, the optional substituents mayfurther be selected from hydroxyl, alkyl, haloalkyl, hyroxyalkyl,alkoxyalkyl, amino, alkylamino and dialkylamino;

wherein

(a) the compound is not one of the following two compounds:

(b) at least one of R^(a1), R^(g2), and R^(b4) is WI;

(c) the compound comprises at least one —P(O)(R^(3A))(R^(3B)); and

(d) the compound further has one or more of the following features:

-   -   Rd is halo(C₃₋₅)cycloalkyl;    -   R^(a2) is halo; substituted alkyl, substituted alkoxy, or        optionally substituted cycloalkyl, wherein substituents on the        alkyl, alkoxy or cycloalkyl groups are selected from halo, amino        and dialkylamino groups;    -   R^(a1) is an optionally substituted 4-membered heterocycle;    -   R^(a1) is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl or        heteroalkyl, and is substituted with one or more groups selected        from halo, OH, heterocyclyl, substituted heterocyclyl,        heteroaryl, and substituted heteroaryl;    -   R^(a1) is heterocyclyl or heterocyclyl-O—, wherein R^(a1) is        substituted with one or more groups selected from —OH, halo,        4-membered heterocyclyl, substituted 4-membered heterocyclyl and        R¹⁸, wherein R¹⁸ is alkyl, alkenyl, alkynyl, cycloalkyl,        cycloalkenyl or heteroalkyl, and R¹⁸ is optionally substituted;    -   R^(a1) and R^(b4), together with the atom to which each is        attached, form an optionally substituted 5-membered heterocyclic        ring;    -   R^(a2) is an optionally substituted 4- to 7-membered membered        heterocycle;    -   R^(b4) is —NR⁷C(O)C(R¹¹)═CR⁹R¹⁰ or —NR⁷C(O)C—C═C—R^(W);    -   R^(g1) is —OR²;    -   R⁹or R¹⁰ is cycloalkyl, —CO₂H, —CO₂-alkyl, —C(O)-heterocyclyl,        —C(O)NH2, —C(O)NH— alkyl or —C(O)N-dialkyl wherein an alkyl,        cycloalkyl or heterocyclyl substituent or portion of a        substituent is optionally substituted with amino, alkylamino,        dialkylamino, alkyl or hydroxyl;    -   one or more of R⁹, R¹⁰ and R¹¹ is halo, haloalkyl, alkyl,        alkoxy, heteroalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,        cycloalkynyl, aryl, heterocyclyl, heterocyclylalkyl, heteroaryl,        heteroarylalkyl or arylalkyl wherein alkyl, heterocylic,        heteroaryl or aryl substituent, or an alkyl, heterocylic,        heteroaryl or aryl portion of a substituent, is optionally        substituted with one or more groups selected from halo,        haloalkyl, hydroxyl, hydroxyalkyl, amino, alkylamino,        dialkylamino, alkyl, alkenyl, SO₂alkyl, oxo, heterocyclyl and        heterocycle substituted with one or more alkyl, amino        alkylamino, dialkylamino, hydroxyl, hydroxyalkyl, SO₂alkyl        substituents; and,    -   R⁹ and R¹¹, taken together with the atom to which each is        attached, form a cycloalkenyl or heterocyclic ring.    -   Unless otherwise specified, (a) each non-cyclic alkyl group        contains 1-6 carbon atoms, each non-cyclic alkenyl or alkynyl        group contains 2-8 carbon atoms, each cycloalkyl and        cycloalkenyl group contains 3-13 carbon atoms, each cycloalkynyl        group contains 8-13 carbon atoms, and each heteroalkyl group is        a branched or unbranched alkyl, alkenyl or alkynyl group of up        to 7 carbon atoms in addition to 1-4 heteroatoms independently        selected from N, O, S and P; (b) each heterocycle is a        non-aromatic ring or ring system having five to fourteen ring        atoms of which one or more, preferably one to four, is each a        heteroatom independently selected from N, O, S or P, and the        remainder of ring atoms are carbon; (c) each aryl group is an        aromatic carbocyclic ring or ring system containing 6-14 ring        atoms; and (d) each heteroaryl moiety is an aromatic ring or        ring system having five to fourteen ring atoms of which one or        more, often one to four, is each a heteroatom independently        selected from N, O, S or P, and the remainder of ring atoms are        carbon. Optional substituents for the various embodiments of the        invention are illustrated in the copious examples and detailed        disclosure below. Briefly, optional substituents for alkyl,        alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl,        heteroalkyl and heterocyclyl moieties include among others,        amino, alkylamino, dialkylamino, aminocarbonyl, halogen, alkyl,        alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, heterocyclyl,        alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminocarbonyloxy,        dialkylaminocarbonyloxy, nitro, cyano, carboxy, alkoxycarbonyl,        alkylcarbonyl, hydroxy, alkoxy, acyloxy, haloalkoxy, ═O, ═S,        ═NH, ═NNR²R³, ═NNHC(O)R², ═NNHCO₂R², ═NNHSO₂R² and —P(O)(R³)₂.        Optional substituents for the aryl and heteroaryl moieties        include among other groups, amino, alkylamino, dialkylamino,        aminocarbonyl, halogen, alkyl, alkenyl, alkynyl, aryl,        heteroaryl, carbocyclyl, heterocyclyl, alkylaminocarbonyl,        dialkylaminocarbonyl, alkylaminocarbonyloxy,        dialkylaminocarbonyloxy, nitro, cyano, carboxy, alkoxycarbonyl,        alkylcarbonyl, hydroxy, alkoxy, acyloxy, and haloalkoxy.    -   The foregoing definitions and non-limiting choices for        substituents are further elaborated upon and exemplified below,        and collectively apply to all subsequent occurrences except to        the extent otherwise specified.

In one embodiment of the compounds of Formula I,

R^(d) is H, halo, CN, alkyl, alkoxy, haloalkyl, alkenyl, haloalkenyl orhalocycloalkyl;

W¹ is —NR⁷C(O)C(R¹¹)═CR⁹R¹⁰, —C(O)C(R¹¹)═CR⁹R¹⁰, —CH₂P(O)C(R¹¹)═CR⁹R¹⁰,—OP(O)C(R⁸)═CR⁹R¹⁰, —NR⁷S(O)₂C(R¹¹)═CR⁹R¹⁰, —NR⁷C(O)C C≡C—R¹⁴,

R^(g) is H, —P(O)(R^(3A))(R^(3B)), —S(O)N(R^(3D))(R^(3D)), —S(O)₂R^(3E),—C(O)N(R^(3F))(R^(3G)), —OC(O)N(R^(3F))(R^(3G)), —NR³HC(O)OR^(3I), a 5-or 6-membered heterocyclic ring comprising 1, 2, 3 or 4 N atoms, whereineach of R^(3A), R^(3B), R^(3D), R^(3D), R^(3E), R^(3F), R^(3G), R^(3H),and R^(3I) is, independently, selected from H, alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, cycloalkynyl, and heteroalkyl, or R^(3A) andR^(3B), or R^(3D) and R^(3D), or R^(3F) and R^(3G), together with theatoms to which each is attached, form an optionally substituted 5- or6-membered heterocyclic ring; and,

R^(g1) is H, F, —P(O)(R^(3A))(R^(3B)), —S(O)N(R^(3D))(R^(3D)),—S(O)₂R^(3E), —C(O)N(R^(3F))(R^(3G)), —OC(O)N(R^(3F))(R^(3G)),—NR³″C(O)OR^(3I), or an optionally substituted 5- or 6-memberedheterocyclic ring; wherein the variable terms are as defined for Formula(I).

In one embodiment of the compounds of the invention and theirpharmaceutically acceptable salts, U¹ is N, U² is C—R^(d), and U³ isC—Re.

In another embodiment U¹ is C—R^(d), U² is N, and U³ is C—R^(e).

In another embodiment U¹ is N, U² is N, and U³ is C—R^(e).

In another embodiment U¹ is N; U² is C—R^(d); U³ is C—R^(e); R^(a2) isOCH₃. R^(g) or R^(g1) is —P(O)(R^(3A))(R^(3B)); each of R^(3A) andR^(3B) is, independently, selected from alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, cycloalkynyl, and heteroalkyl, or R^(3A) andR^(3B), together with the atom to which each is attached, form a 5- or6-membered heterocyclic ring which is unsubstituted or substituted;R^(b4) is W¹ as defined in Formula (I). In one class of these compoundsV¹ is NH. In another V¹ is O. In certain embodiments of both classesR^(d) is Cl. In certain embodiments of both classes R^(g) or R^(g1) is—P(O)(CH₃)₂ or —P(O)(CH₂CH₃)₂.

In another embodiment U³ is N, one of U¹ and U² is N, and the other isC—R^(d).

Certain compounds of the invention are described by any of Formulas(IIIa)-(IIIe), or a pharmaceutically acceptable salt thereof:

wherein R^(a1); R^(a2); R^(b2); R^(b4); R^(g); R^(g1); R^(g2); R^(d);and R^(h) are as defined in Formula (I).

Other embodiments are described by any of Formulas (IVa)-(IVe), or apharmaceutically acceptable salt thereof:

wherein R^(a2); R^(b2); R^(b4); R^(g); R^(g1); R^(g2); R^(d); and R^(h)are as defined in Formula (I).

Further embodiments are described by any of Formulas (Va)-(Ve), or apharmaceutically acceptable salt thereof:

wherein R^(a1); R^(a2); R^(b2); R^(b4); R^(g); R^(g1); R^(g2); R^(d);and R^(h) are as defined in Formula (I).

Other embodiments are described by any of Formulas (VIa)-(VIe), or apharmaceutically acceptable salt thereof:

wherein R^(a2); R^(b2); R^(b4); R^(g); R^(g1); R^(g2); R^(d); and R^(h)are as defined in Formula (I), and R^(a1) is selected from W¹, —R¹,—C(O)YR², —C(═S)YR², —C(═NR¹)YR², —C(═N—OR¹)YR², —C(═N—NR¹R²)YR²,—S(O)_(r)R², and

each Y is, independently, a bond, —O—, —S— or —NR¹—;

each occurrence of R¹ and R² is, independently, selected from H, alkyl,alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl,heteroalkyl, heterocyclic and heteroaryl; each of X₁ and X₂ is,independently, selected from CH and N;

W¹ is as defined in Formula (I); and

R⁴ is selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,cycloalkynyl, aryl, heteroalkyl, heterocyclic and heteroaryl.

Certain embodiments in which Ring A is cyclopentyl are described by anyof Formulas (VIIa)-(VIIe), or a pharmaceutically acceptable saltthereof:

wherein R^(a1); R^(a2); R^(b4); R^(g); R^(g1); R^(g2); R^(d); and R^(h)are as defined in Formula (I).

Other embodiments are described by any of Formulas (VIIIa)-(VIIIe), or apharmaceutically acceptable salt thereof:

wherein R^(a2); R^(b2); R^(g); R^(g1); R^(g2); R^(d); and R^(h) are asdefined in Formula (I), R^(a1) is selected from W¹, —R¹, —C(O)YR²,—C(═S)YR², —C(═NR¹)YR², —C(═N−OR¹)YR², —C(═N—NR¹R²)YR², —S(O)_(r)R², and

each Y is, independently, a bond, —O—, —S— or —NR¹—;

W¹ is as defined in Formula (I);

each occurrence of R¹ and R² is, independently, selected from H, alkyl,alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl,heteroalkyl, heterocyclic and heteroaryl;

-   -   each of X₁ and X₂ is, independently, selected from CH and N; and        R⁴ is selected from alkyl, alkenyl, alkynyl, cycloalkyl,        cycloalkenyl, cycloalkynyl, aryl, heteroalkyl, heterocyclic and        heteroaryl.

Further embodiments are described by any of Formulas (IXa)-(IXe), or apharmaceutically acceptable salt thereof:

wherein R^(a1) is W¹, —R¹, —C(O)YR², —C(═S)YR², —C(═NR¹)YR²,—C(═N—OR¹)YR², —C(═N—NR¹R²)YR², —S(O)_(r)R², or

each Y is, independently, a bond, —O—, —S— or —NR¹—;

R^(b2); R^(b4); R^(g); R^(g1); R^(g2); R^(d); R^(h) and W¹ are asdefined in Formula (I);

each occurrence of R¹ and R² is, independently, selected from H, alkyl,alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl,heteroalkyl, heterocyclic and heteroaryl;

each of X₁ and X₂ is, independently, CH or N; and

R⁴ is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl,aryl, heteroalkyl, heterocyclic or heteroaryl.

Other embodiments are described by described by any of Formulas(Xa)-(Xe), or a pharmaceutically acceptable salt thereof:

wherein R^(b2); R^(b4); R^(g); R^(g1); R^(g2); R^(d); and R^(h) are asdefined in Formula (I), R^(a1) is selected from W¹, —R¹, —C(O)YR²,—C(═S)YR², —C(═NR¹)YR², —C(═N—OR¹)YR², —C(═N—NR¹R²)R², —S(O)_(r)R², and

each Y is, independently, a bond, —O—, —S— or —NR¹—;

W¹ is as defined in Formula (I);

each occurrence of R¹ and R² is, independently, selected from H, alkyl,alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl,heteroalkyl, heterocyclic and heteroaryl;

each of X₁ and X₂ is, independently, selected from CH and N; and R⁴ isselected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,cycloalkynyl, aryl, heteroalkyl, heterocyclic and heteroaryl.

[1] In one embodiment of any of the Formulas above, i.e., any of FormulaI, III(a)-(e), IV(a)-(e), V(a)-(e), VI(a)-(e), VII(a)-(e), VIII(a)-(e),IX(a)-(e), and X(a)-(e), R^(a2) is H, F, Cl, —CH₃, —CF₃, —CH₂CH₃, —OCH₃,—OCF₃, —OCH₂CH₃ or -heterocyclyl-O—, e.g., a 4-membered heterocyclyl.

[2] In certain embodiments of any of Formulas I, III(a)-(e), IV(a)-(e),V(a)-(e), VI(a)-(e), VII(a)-(e), VIII(a)-(e), IX(a)-(e), and X(a)-(e),including among others the embodiment immediately above, R^(d) is H, Cl,F, Br, I, CN, CH₃, CF₃, cyclopropyl or —CH₂CH₂═CH₂.

[3] In particular embodiments of any of Formulas I, III(a)-(e),IV(a)-(e), V(a)-(e), VI(a)-(e), VII(a)-(e), VIII(a)-(e), IX(a)-(e), andX(a)-(e), including among others each of the embodiments immediatelyabove, R^(b2) is H.

[4] In certain embodiments of any of Formulas I, III(a)-(e), IV(a)-(e),V(a)-(e), VI(a)-(e), VII(a)-(e), VIII(a)-(e), IX(a)-(e), and X(a)-(e),including among others each of the embodiments immediately above, R^(g1)is H and R^(g2) is H, F, C₁₋₆ alkyl, or C₁₋₆ alkoxy.

[5] In certain embodiments of any of Formulas I, III(a)-(e), IV(a)-(e),V(a)-(e), VI(a)-(e), VII(a)-(e), VIII(a)-(e), IX(a)-(e), and X(a)-(e),including among others each of the embodiments immediately above, R^(g)is —P(O)(R^(3A))(R^(3B)), wherein R^(3A) and R^(3B), are as defined inFormula (I). In some cases R^(g) is —P(O)(CH₃)₂ or —P(O)(CH₂CH₃)₂.

[6] In certain embodiments of any of Formulas I, III(a)-(e), IV(a)-(e),V(a)-(e), VI(a)-(e), VII(a)-(e), VIII(a)-(e), IX(a)-(e), and X(a)-(e),including among others each of the first four embodiments immediatelyabove, R^(g) is —S(O)₂R^(3E)), wherein R^(3E) is as defined in Formula(I). For example, in some cases R^(g) is —S(O)₂CH(CH₃)₂.

[7] In certain embodiments of any of Formulas I, III(a)-(e), IV(a)-(e),V(a)-(e), VI(a)-(e), VII(a)-(e), VIII(a)-(e), IX(a)-(e), and X(a)-(e),including among others each of the embodiments immediately above, R^(a1)is a 5- or 6-membered heteroaryl ring optionally substituted with an—OH, halo, alkyl, substituted alkyl substituent.

[8] In certain embodiments of any of Formulas I, III(a)-(e), IV(a)-(e),V(a)-(e), VI(a)-(e), VII(a)-(e), VIII(a)-(e), IX(a)-(e), and X(a)-(e),including among others each of the first six embodiments immediatelyabove, R^(a1) is a 4-, 5-, 6- or 7-membered heterocycle which isoptionally substituted with one or more groups selected from halo andR¹⁷. R¹⁷ is an alkyl, cycloalkyl, heteroalkyl, 4- to 7-memberedheterocyclyl or heteroaryl group, and R¹⁷ is optionally substituted withone or more halo, alkyl, cycloalkyl, heterocyclic or heteroaryl groups,of which, the cycloalkyl, heterocyclic or heteroaryl substituent isoptionally substituted with one or more halo, alkyl, haloalkyl,hydroxyalkyl, amino, dialkylamino or cycloalkyl groups.

In one class of compounds of the foregoing embodiment, R^(a1), isselected from the following:

[9] In other embodiments of any of Formulas I, III(a)-(e), IV(a)-(e),V(a)-(e), VI(a)-(e), VII(a)-(e), VIII(a)-(e), IX(a)-(e), and X(a)-(e),including among others each of the first six embodiments immediatelyabove, R^(a1) is —OR², as defined in Formula (I). For example, R^(a1) isselected from the following:

[10] In certain embodiments of any of Formulas I, III(a)-(e), IV(a)-(e),V(a)-(e), VI(a)-(e), VII(a)-(e), VIII(a)-(e), IX(a)-(e), and X(a)-(e),including among others each of the first six embodiments immediatelyabove, R^(a1) is an optionally substituted alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, cycloalkynyl, or heteroalkyl group, whereinoptional substituents are selected from halo, cycloalkyl, heterocyclicor heteroaryl groups, wherein said cycloalkyl, heterocyclic andheteroaryl substituent(s) are independently optionally substituted withone or more halo, alkyl, haloalkyl, hydroxyalkyl, amino, dialkylamino orcycloalkyl groups. For example, R^(a1) may be selected from thefollowing:

In other embodiments of any of Formulas I, III(a)-(e), IV(a)-(e),V(a)-(e), VI(a)-(e), VII(a)-(e), VIII(a)-(e), IX(a)-(e), and X(a)-(e),including among others each of the first six embodiments immediatelyabove, R^(a1) is of the Formula:

wherein:

J¹ and J² are independently H, halo or R^(J); or J¹ and J² together withthe atom to which each is attached form an optionally substituted ringwhich is C₃₋₈ cycloalkyl, 3- to 7-membered heterocyclic, or heteroaryl;

J³ and J⁴ are independently H or R^(J); or J³ and J⁴ together with theatom to which each is attached form an optionally substituted ring whichis 3- to 7-membered heterocyclic or heteroaryl ring;

R^(J) is C₁₋₆ alkyl, C₃₋₈ cycloalkyl, C₁₋₈ heteroalkyl, or 3- to7-membered heterocyclyl, wherein each R^(J) is independently selectedfrom halo, haloalkyl, hydroxyl, hydroxyalkyl, amino, alkylamino,dialkylamino, cycloalkyl, alkoxy, cycloalkoxy and heterocyclic groups,wherein the alkyl, cycloalkyl, and heterocyclic groups on R^(J) areoptionally substituted with one or more halo, alkyl, haloalkyl,hydroxyalkyl, alkoxyalkyl, amino, alkylamino, dialkylamino or cycloalkylgroups; and, z is 1-3.

By way of non-limiting example, R^(a1) may be selected from thefollowing:

In particular embodiments of any of Formulas I, III(a)-(e), IV(a)-(e),V(a)-(e), VI(a)-(e), V(IIa)-(e), VIII(a)-(e), IX(a)-(e), and X(a)-(e),including among others each of the embodiments immediately above, R^(b4)is —NR⁷C(O)C(R¹¹)═CR⁹R¹⁰, —NR⁷S(O)₂C(R⁹)(R¹⁰)(R^(X)), —NR⁷C(O)C≡C—R¹⁴,Or —NR⁷C(O)C(R⁹)(R¹⁰)(R^(X)), wherein R⁷, R⁹, R¹⁰, R¹¹, R¹⁴, and R^(X)are as defined in Formula (I).

For example, in cases in which R^(b4) may be —NHC(O)CH═CH₂ or may beselected from the following:

In other embodiments R^(b4) is —NHC(O)C≡CH or may be selected from thefollowing:

In one class of compounds of any of Formulas I, III(a)-(e), IV(a)-(e),V(a)-(e), VI(a)-(e), VII(a)-(e), VIII(a)-(e), IX(a)-(e), and X(a)-(e),and their pharmaceutically acceptable salts, including compounds withthe various R^(a1) groups disclosed above, R^(b4) is W¹ as defined inFormula (I). In one subclass thereof, R^(a2) is H, halo, —CH₃, —CF₃,—CH₂CH₃, —OCH₃, —OCF₃, —OCH₂CH₃, —OCH₂CH₂N(CH₃)₂ or —O-heterocyclyl. Ina particular embodiment of that subclass, R^(g) is—P(O)(R^(3A))(R^(3B)), wherein R^(3A) and R^(3B), are as defined inFormula (I), e.g., R^(g) is —P(O)(CH₃)₂ or —P(O)(CH₂CH₃)₂. In anotherembodiment of that subclass, R^(g) is —S(O)₂R^(3E)), wherein R^(3E) isas defined in Formula (I), e.g., R^(g) is —S(O)₂CH(CH₃)₂. In eitherembodiment of the subclass, R^(d) may be CI, F, Br, I, or CH₃.

In certain embodiments of any of the above formulas, R^(g1) is H andR^(g2) is H, F, C₁₋₆ alkyl, or C₁₋₆ alkoxy.

In particular embodiments of any of the above formulas, R^(g) is—P(O)(R^(3A))(R^(3B)) or —S(O)₂R^(3E), wherein R^(3A); R^(3B); andR^(3E) are as defined in formula (I). For example, R^(g) can be selectedfrom —P(O)(CH₃)₂ and —S(O)₂(CH(CH₃)₂).

In certain embodiments of any of the above formulas, R^(a1) is a 5 or 6member heterocyclic ring including 1 or 2 N or O atoms which isunsubstituted or substituted with an alkyl group. For example, R^(a1)can be selected from any of the following groups:

In particular embodiments of any of the above formulas, R^(a2) ismethoxy; R^(d) is CI, F, Br, I, or CH₃; and R^(g) is —P(O)(CH₃)₂ or—S(O)₂(CH(CH₃)₂).

In certain embodiments of the compounds of formula (I), U¹ is N, U² isC—R^(d), and U³ is C—R^(e); U¹ is C—R^(d), U² is N, and U³ is C—R^(e);U¹ is N, U² is N, and U³ is C—R^(e); or U³ is N, one of U¹ and U² is N,and the other is C—R^(d).

In still other embodiments of the compounds of formula (I), U¹ is N; U²is C—R^(d); U³ is C—R^(e); R^(a2) is OCH₃; R^(g) or R^(g1) is—P(O)(R^(3A))(R^(3B)); each of R^(3A) and R^(3B) is, independently,selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,cycloalkynyl, and heteroalkyl, or R^(3A) and R^(3B), together with theatoms to which they are attached, combine to form a 5- or 6-memberedheterocyclic ring which is unsubstituted or substituted; R^(b4) is—NHC(O)C(R¹¹)═CR⁹R¹⁰; each occurrence of R⁹ and R¹⁰ is, independently,selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,cycloalkynyl, aryl, heteroalkyl, heterocyclic and heteroaryl; R¹¹ is—C(O)—OR¹², —CH₂N(CH₃)₂, H, alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, cycloalkynyl, aryl, heteroalkyl, heterocyclic, orheteroaryl; and R¹² is alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, cycloalkynyl, aryl, heteroalkyl, heterocyclic, orheteroaryl. Exemplary compounds include those in which V¹ is NH, V¹ isO, R^(d) is Cl, R^(g) or R^(g1) is —P(O)(CH₃)₂ or —P(O)(CH₂CH₃)₂, and/orR^(b4) is —NHC(O)C(R¹¹)═CH₂. In particular embodiments, R^(b4) is—NHC(O)C(R¹¹)═CH₂; R¹¹ is —C(O)—OR¹², —CH₂N(CH₃)₂, H, alkyl, alkenyl,alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroalkyl,heterocyclic, or heteroaryl; R¹² is alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, cycloalkynyl, aryl, heteroalkyl, heterocyclic, orheteroaryl; R^(d) is Cl; and R^(g) or R^(g1) is selected from—P(O)(CH₃)₂ and —P(O)(CH₂CH₃)₂.

In one embodiment of the compounds of any of Formulas (I), (Ia)-(Ic),(IIa)-(IIc), (IIIa)-(IIIe), (IVa)-(IVe), (Va)-(Ve), (VIa)-(VIe),(VIIIa)-(VIIIe), (IXa)-(IXe), and (Xa)-(Xe), R^(b4) is —NHC(O)CH═CH₂.

DETAILED DESCRIPTION

The invention features a method for treating an EGFR-driven cancer in asubject by administering to the subject a therapeutically effectiveamount of a compound of the invention, or a pharmaceutically acceptablesalt thereof.

In a related aspect, the invention features a method for treating anEGFR-driven cancer in a subject, the method including (a) providing asubject having an EGFR-driven cancer characterized by the presence of amutation in epidermal growth factor receptor kinase (EGFR), and (b)administering to the subject a therapeutically effective amount of acompound of the invention, or a pharmaceutically acceptable saltthereof. In certain embodiments, EGFR-driven cancer is characterized bythe presence of one or more mutations selected from: (i) L858R, (ii)T790M, (iii) both L858R and T790M, (iv) delE746_A750, and (v) bothdelE746_A750 and T790M.

In the above methods, the EGFR-driven cancer can be a non-small celllung cancer (NSCLS); glioblastoma; pancreatic cancer; head and neckcancer (e.g., squamous cell carcinoma); breast cancer; colorectalcancer; epithelial cancer; ovarian cancer; prostate cancer; anadenocarcinoma, or any EGFR-driven cancer described herein.

In certain embodiments of the above methods, the method further includesadministering to the subject a first kinase inhibitor selected fromerlotinib, gefitinib, and pharmaceutically acceptable salts thereof,within 6 days (e.g., within 2 weeks, 1 week, 6 days, 5 days, 4 days, 3days, 2 days, 1 day, or simultaneously) of administering the compound ofthe invention (e.g., a compound of any of Formulas (I), (Ia)-(Ic),(IIa)-(IIc), (IIIa)-(IIIe), (IVa)-(IVe), (Va)-(Ve), (VIa)-(VIe),(VIIIa)-(VIIIe), (IXa)-(IXe), and (Xa)-(Xe)), wherein each of thecompound of the invention and the first kinase inhibitor areadministered in an amount that together is sufficient to treat theEGFR-driven cancer.

In a related aspect, the invention features a method of inhibiting theproliferation of a cell expressing an EGFR mutant, the method includingcontacting the cell with a compound of the invention, or apharmaceutically acceptable salt thereof, in an amount sufficient toinhibit the proliferation. For example, the EGFR mutant can becharacterized by the presence of one or more mutations in epidermalgrowth factor receptor kinase (EGFR) selected from: (i) L858R, (ii)T790M, (iii) both L858R and T790M, (iv) delE746_A750, (v) bothdelE746_A750 and T790M, and any other EGFR mutations described herein.In certain embodiments, the cell is a cancer cell (e.g., a cell from anon-small cell lung cancer (NSCLS); glioblastoma; pancreatic cancer;head and neck cancer (e.g., squamous cell carcinoma); breast cancer;colorectal cancer; epithelial cancer; ovarian cancer; prostate cancer;an adenocarcinoma, or any other EGFR expressing cancer describedherein).

The invention further features a method of treating an EGFR-drivencancer refractory to a first kinase inhibitor selected from erlotinib,gefitinib, and pharmaceutically acceptable salts thereof, in a subjectby administering to the subject a compound of the invention, or apharmaceutically acceptable salt thereof, in an amount sufficient totreat the cancer.

In any of Formulas I, III(a)-(e), IV(a)-(e), V(a)-(e), VI(a)-(e),VII(a)-(e), VIII(a)-(e), IX(a)-(e), and X(a)-(e), the compound can beeither in its free base form, or a pharmaceutically acceptable salt.

The response criteria for the methods of the invention can be gradedaccording to the response evaluation criteria in solid tumors (RECIST)guidelines (see Eur. J. Cancer 45:228 (2009)) that define when cancerpatients improve (“respond”), stay the same (“stabilize”), or worsen(“progression”) during treatments. A complete response is characterizedby: (i) disappearance of all target lesions; and (ii) any pathologicallymph nodes (whether target or non-target) must have reduction in shortaxis to <10 mm. A partial response is characterized by: (i) at least a30% decrease in the sum of diameters of target lesions, taking asreference the baseline sum diameters. A progressive disease ischaracterized by (i) at least a 5%, 10%, or 20% increase in the sum ofdiameters of target lesions, taking as reference the smallest sum onstudy (this includes the baseline sum if that is the smallest on study);or (ii) the appearance of one or more new lesions.

The term “administration” or “administering” refers to a method ofgiving a dosage of a pharmaceutical composition to a mammal, where themethod is, e.g., oral, intravenous, intraperitoneal, intraarterial, orintramuscular. The preferred method of administration can vary dependingon various factors, e.g., the components of the pharmaceuticalcomposition, site of the potential or actual disease and severity ofdisease.

By “EGFR-driven cancer” is meant a cancer characterized byinappropriately high expression of an EGFR gene or by a mutation in anEGFR gene that alters the biological activity of an EGFR nucleic acidmolecule or polypeptide. EGFR-driven cancers can arise in any tissue,including brain, blood, connective tissue, liver, mouth, muscle, spleen,stomach, testis, and trachea. EGFR-driven cancers can include non-smallcell lung cancer (NSCLS), including one or more of squamous cellcarcinoma, adenocarcinoma, adenocarcinoma, bronchioloalveolar carcinoma(BAC), BAC with focal invasion, adenocarcinoma with BAC features, andlarge cell carcinoma; neural tumors, such as glioblastomas; pancreaticcancer; head and neck cancers (e.g., squamous cell carcinoma); breastcancer; colorectal cancer; epithelial cancer, including squamous cellcarcinoma; ovarian cancer; prostate cancer; adenocarcinomas; andincluding cancers which are EGFR mediated.

An “EGFR mutant” or “mutant” includes one or more deletions,substitutions, or additions in the amino acid or nucleotide sequences ofEGFR protein, or EGFR coding sequence. The EGFR mutant can also includeone or more deletions, substitutions, or additions, or a fragmentthereof, as long as the mutant retains or increases tyrosine kinaseactivity, compared to wild type EGFR. In particular EGFR mutations,kinase or phosphorylation activity can be increased (e.g., by at least5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or even 100%), ascompared to wild type EGFR. Particular EGFR mutants are describedherein, where mutations are provided relative to the position of anamino acid in human EGFR, as described in the sequence provided in NCBIGenBank Reference Sequence: NP_(—)005219.2.

As used herein, the term “inhibiting the proliferation of a cellexpressing an EGFR mutant” refers to measurably slowing, stopping, orreversing the growth rate of the EGFR-expressing cells in vitro or invivo. Desirably, a slowing of the growth rate is by at least 10%, 20%,30%, 50%, or even 70%, as determined using a suitable assay fordetermination of cell growth rates (e.g., a cell growth assay describedherein). The EGFR mutant can be any EGFR mutant described herein.

As used herein, the term “refractory” refers to a cancer which isprogressive in response to a given particular therapy. The cancer can berefractory either from the initial administration of the therapy; orbecome refractory over time in response to the therapy.

The term “sequence identity” is meant the shared identity between two ormore nucleic acid sequence, or two or more amino acid sequences,expressed in the terms of the identity between the sequences. Sequenceidentity can be measured in terms of percentage identity; the higher thepercentage, the more identical the sequences are. Homologs or orthologsof nucleic acid or amino acid sequences possess a relatively high degreeof sequence identity when aligned using standard methods. Methods ofalignment of sequences for comparison are well known in the art. Variousprograms and alignment algorithms are described in: Smith and Watermann,Adv. Appl. Math. 2:482 (1981); Needleman and Wunsch, J. Mol. Biol.48:443 (1970); Pearson and Lipman, Proc. Natl. Acad. Sci. U.S.A. 85:2444(1988); Corpet et al., Nuc. Acid Res. 16:10881 (1988); Huang et al.,Computer Appls. in the Biosciences 8:155 (1992); and Pearson et al.,Meth. Mol. Biol. 24:307 (1994). Altschul et al. (J. Mol. Biol. 215:403(1990)) presents a detailed consideration of sequence alignment methodsand homology calculations. The NCBI Basic Local Alignment Search Tool(BLAST) (Altschul et al., J. Mol. Biol. 215:403 (1990)) is availablefrom several sources, including the National Center for BiologicalInformation (NCBI) website, for use in connection with the sequenceanalysis programs blastp, blastn, blastx, tblastn, and tblastx.Additional information can be found at the NCBI website. BLASTN is usedto compare nucleic acid sequences, while BLASTP is used to compare aminoacid sequences. To compare two nucleic acid sequences, the option can beset as follows: −i is set to a file containing the first nucleic acidsequence to be compared; −j is set to a file containing the secondnucleic acid sequence to be compared; −p is set to blastn; −o is set toany desired file name; −q is set to −1; −r is set to 2; and all otheroptions are left at their default setting. Once aligned, the number ofmatches is determined by counting the number of positions where anidentical nucleotide or amino acid residue is present in both sequences.The percent sequence identity is determined by dividing the number ofmatches either by the length of the sequence set forth in the identifiedsequence, or by an articulated length (such as 30, 35, 40, 45, 50, 60,70, 80, 90, 100, 150, 200, 250, 300, 350, or 400 consecutive nucleotidesor amino acid residues from a sequence set forth in an identifiedsequence), followed by multiplying the resulting value by 100. Oneindication that two nucleic acid molecules are closely related is thatthe two molecules hybridize to each other under stringent conditions.Stringent conditions are sequence-dependent and are different underdifferent environmental parameters.

Nucleic acid molecules that hybridize under stringent conditions to anEGFR gene sequence typically hybridize to a probe based on either anentire EGFR gene or selected portions of the gene (e.g., the kinasedomain or a segment of the gene that contains the mutated codonsdescribed herein), under conditions described above.

As used herein, the term “treating” refers to administering apharmaceutical composition for prophylactic and/or therapeutic purposes.To “prevent disease” refers to prophylactic treatment of a subject whois not yet ill, but who is susceptible to, or otherwise at risk of, aparticular disease. To “treat disease” or use for “therapeutictreatment” refers to administering treatment to a subject alreadysuffering from a disease to improve or stabilize the subject'scondition. Thus, in the claims and embodiments, treating is theadministration to a subject either for therapeutic or prophylacticpurposes.

Where optional substitution of compounds of the invention is indicated,but one or more optional substituents is not specified, the substituentmay be selected from those disclosed herein as generally appropriate inthe given context, e.g. on an alkyl carbon, an aryl carbon, etc., andspecifically include substitution exemplified in the examples. Otherparameters of functional groups are also disclosed in detail below.

The term “alkyl” refers to linear, branched, cyclic, and polycyclic nonaromatic hydrocarbon groups, which may be substituted or unsubstituted.Unless otherwise specified, “alkyl” groups contain one to eight, andtypically one to six carbon atoms. Examples of alkyl include, withoutlimitation, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, butyl,isobutyl, sec-butyl, tert-butyl, cyclobutyl, pentyl, isopentyltert-pentyl, cyclopentyl, hexyl, isohexyl, cyclohexyl, and n-heptyl,among others. Exemplary substituted alkyl groups include, withoutlimitation, haloalkyl groups (e.g., fluoromethyl, difluoromethyl,trifluoromethyl, 2-fluoroethyl, 3-fluoropropyl), hydroxymethyl,2-hydroxyethyl, 3-hydroxypropyl, benzyl, substituted benzyl, andphenethyl, among others. Note that as used herein, “alkyl” encompassescyclic alkyl groups, which if not otherwise specified, contain 3-8carbon atoms.

The term “alkoxy” refers to a subset of alkyl in which an alkyl group asdefined above with the indicated number of carbons attached through anoxygen bridge, —O-alkyl, wherein the alkyl group contains 1 to 8 carbonsatoms and is substituted or unsubstituted. Exemplary alkoxy groupsinclude, without limitation, methoxy, ethoxy, n-propoxy, i-propoxy,t-butoxy, n-butoxy, s-pentoxy, —OCF₃, and —O-cyclopropyl.

The term “haloalkyl” refers to a subset of alkyl in which an alkyl groupas defined above having one or more hydrogen atoms of the alkylsubstituted with a halogen atom. Exemplary haloalkyl groups include,without limitation, fluoromethyl, trifluoromethyl, trichloromethyl,pentafluoroethyl and the like.

The term “alkenyl” refers to a branched or unbranched hydrocarbon groupcontaining one or more double bonds and having from 2 to 8 carbon atoms.An alkenyl may optionally include monocyclic or polycyclic rings, inwhich each ring desirably has from three to six members. The alkenylgroup may be substituted or unsubstituted. Alkenyl groups include,without limitation, vinyl, allyl, 2-cyclopropyl-1-ethenyl, 1-propenyl,1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-1-propenyl, and2-methyl-2-propenyl.

The term “alkynyl” refers to a branched or unbranched hydrocarbon groupcontaining one or more triple bonds and having from 2 to 8 carbon atoms.The alkynyl group may be substituted or unsubstituted. Alkynyls include,without limitation, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl,2-butynyl, and 3-butynyl.

The term “cycloalkyl” refers to cyclic or polycyclic hydrocarbon groupsof from 3 to 13 carbon atoms, any of which is saturated. Cycloalkylgroups may be substituted or unsubstituted. Exemplary cycloalkyl groupsinclude, without limitation, cyclopropyl, norbornyl,[2.2.2]bicyclooctane, and [4.4.0]bicyclodecane, and the like, which, asin the case of other alkyl moieties, may optionally be substituted.

The term “cycloalkenyl” refers to cyclic or polycyclic hydrocarbongroups of from 3 to 13 carbon atoms, preferably from 5 to 8 carbonatoms, containing one or more double bonds. Cycloalkenyl groups may besubstituted or unsubstituted. Exemplary cycloalkenyl groups include,without limitation, cyclopentenyl, cyclohexenyl, and cyclooctenyl.

The term “cycloalkynyl” refers to cyclic or polycyclic hydrocarbongroups of from 5 to 13 carbon atoms containing one or more triple bonds.Cycloalkynyl groups may be substituted or unsubstituted.

The term “heteroalkyl” means a branched or unbranched alkyl, alkenyl, oralkynyl group having from 1 to 14 carbon atoms in addition to 1, 2, 3 or4 heteroatoms independently selected from the group consisting of N, O,S, and P. Heteroalkyls include, without limitation, tertiary amines,secondary amines, ethers, thioethers, amides, thioamides, carbamates,thiocarbamates, hydrazones, imines, phosphodiesters, phosphoramidates,sulfonamides, and disulfides. A heteroalkyl may optionally includemonocyclic, bicyclic, or tricyclic rings, in which each ring desirablyhas three to six members. The heteroalkyl group may be substituted orunsubstituted. Examples of heteroalkyls include, without limitation,polyethers, such as methoxymethyl and ethoxyethyl.

As used herein, “heterocyclic ring” and “heterocyclyl” refer tonon-aromatic ring systems having five to fourteen ring atoms in whichone or more ring carbons, preferably one to four, are each replaced by aheteroatom such as N, O, S, or P, which may be used alone or as part ofa larger moiety as in “heterocyclyl-alkyl” (a heterocyclyl-substitutedC₁₋₆ alkyl), “heterocyclyl-alkoxy” (a heterocyclyl-substituted C₁₋₆alkoxy), or “heterocycloxy-alkyl” (a heterocycloxy-substituted C₁₋₆alkyl), and includes aralkyl, aralkoxy, and aryloxyalkyl groups.Heterocyclic rings may be substituted or unsubstituted and may includeone, two, or three fused or unfused ring systems. Desirably, theheterocyclic ring is a 5- to 7-membered monocyclic or 7- to 14-memberedbicyclic heterocyclic ring consisting of 2 to 6 carbon atoms and 1, 2,3, or 4 heteroatoms independently selected from N, O, and S andincluding any bicyclic group in which any of the above-definedheterocyclic rings is fused to a benzene ring. Exemplary heterocyclicrings include, without limitation, 3-1H-benzimidazol-2-one,(1-substituted)-2-oxo-benzimidazol-3-yl, 2-tetrahydrofuranyl,3-tetrahydrofuranyl, 2-tetrahydrothiophenyl, 3-tetrahydrothiophenyl,2-morpholinyl, 3-morpholinyl, 4-morpholinyl, 2-thiomorpholinyl,3-thiomorpholinyl, 4-thiomorpholinyl, 1-pyrrolidinyl, 2-pyrrolidinyl,3-pyrrolidinyl, 1-piperazinyl, 2-piperazinyl, 1-piperidinyl,2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 4-thiazolidinyl,diazolonyl, N-substituted diazolonyl, 1-phthalimidinyl, benzoxanyl,benzopyrrolidinyl, benzopiperidinyl, benzoxolanyl, benzothiolanyl, andbenzothianyl. A heterocyclyl group can include two or more of the ringsystems listed above. Heterocyclic rings include those in which anon-aromatic heteroatom-containing ring is fused to one or more aromaticor non-aromatic rings, such as in an indolinyl, chromanyl,phenanthridinyl, or tetrahydroquinolinyl, where the radical or point ofattachment is on the non-aromatic heteroatom-containing ring.

The term “aryl” used alone or as part of a larger moiety as in “aralkyl”(an aryl-substituted C₁₋₆ alkyl), “aralkoxy” (an aryl-substituted C₁₋₆alkoxy), or “aryloxyalkyl” (an aryloxy-substituted C₁₋₆ alkyl), refersto aromatic monocyclic or polycyclic ring groups having six to fourteenring atoms, such as phenyl, 1-naphthyl, 2-naphthyl, 1-anthracyl, and2-anthracyl and includes aralkyl, aralkoxy, and aryloxyalkyl groups. An“aryl” ring may be substituted or unsubstituted. The term “aryl”includes fused polycyclic aromatic ring systems in which an aromaticring is fused to one or more rings. Non-limiting examples of aryl groupsinclude phenyl, hydroxyphenyl, halophenyl, alkoxyphenyl, dialkoxyphenyl,trialkoxyphenyl, alkylenedioxyphenyl, naphthyl, phenanthryl, anthryl,phenanthro, 1-naphthyl, 2-naphthyl, 1-anthracyl, and 2-anthracyl. Alsoincluded within the scope of the term “aryl”, as it is used herein, is agroup in which an aromatic ring is fused to one or more non-aromaticrings, such as in a indanyl, phenanthridinyl, or tetrahydronaphthyl,where the radical or point of attachment is on the aromatic ring.

The term “heteroaryl” as used herein refers to stable heterocyclic, andpolyheterocyclic aromatic moieties having 5-14 ring atoms. Heteroarylgroups may be substituted or unsubstituted and include both monocyclicand polycyclic ring systems. Examples of typical heteroaryl ringsinclude 5-membered monocyclic rings, such as thienyl, pyrrolyl,imidazolyl, pyrazolyl, furyl, isothiazolyl, furazanyl, isoxazolyl, andthiazolyl; 6-membered monocyclic rings, such as pyridyl, pyrazinyl,pyrimidinyl, pyridazinyl, and triazinyl; and polycyclic heterocyclicrings, such as benzo[b]thienyl, naphtho[2,3-b]thienyl, thianthrenyl,isobenzofuranyl, chromenyl, xanthenyl, phenoxathienyl, indolizinyl,isoindolyl, indolyl, indazolyl, purinyl, isoquinolyl, quinolyl,phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, benzothiazole,benzimidazole, tetrahydroquinoline cinnolinyl, pteridinyl, carbazolyl,beta-carbolinyl, phenanthridinyl, acridinyl, perimidinyl,phenanthrolinyl, phenazinyl, isothiazolyl, phenothiazinyl, andphenoxazinyl (see e.g. Katritzky, Handbook of Heterocyclic Chemistry).Exemplary heteroaryl rings include, without limitation, 2-furanyl,3-furanyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl,3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxadiazolyl, 5-oxadiazolyl,2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl,2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl,3-pyridazinyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 5-tetrazolyl,2-triazolyl, 5-triazolyl, 2-thienyl, 3-thienyl, carbazolyl,benzimidazolyl, benzothienyl, benzofuranyl, indolyl, quinolinyl,benzotriazolyl, benzothiazolyl, benzooxazolyl, benzimidazolyl,isoquinolinyl, indolyl, isoindolyl, acridinyl, and benzoisoxazolyl.Heteroaryl groups further include a group in which a heteroaromatic ringis fused to one or more aromatic or nonaromatic rings where the radicalor point of attachment is on the heteroaromatic ring, such astetrahydroquinoline, tetrahydroisoquinoline, andpyrido[3,4-d]pyrimidinyl, imidazo[1,2-a]pyrimidyl,imidazo[1,2-a]pyrazinyl, imidazo[1,2-a]pyiridinyl,imidazo[1,2-c]pyrimidyl, pyrazolo[1,5-a][1,3,5]triazinyl,pyrazolo[1,5-c]pyrimidyl, imidazo[1,2-b]pyridazinyl,imidazo[1,5-a]pyrimidyl, pyrazolo[1,5-b][1,2,4]triazine, quinolyl,isoquinolyl, quinoxalyl, imidazotriazinyl, pyrrolo[2,3-d]pyrimidyl,triazolopyrimidyl, and pyridopyrazinyl.

An aryl group or heteroaryl group may contain one or more substituents.Exemplary substituents for aryl or heteroaryl group include halogen (F,Cl, Br or I), alkyl, alkenyl, alkynyl, heteroalkyl, —NO₂, —CN, —R^(A),—OR^(B), —S(O)_(r)R^(B), (wherein r is 0, 1 or 2), —SO₂NR^(A)R^(B),—NR^(A)R^(B), —O—NR^(A)R^(B), —NR^(A)—NR^(A)R^(B), —(CO)YR^(B),—O(CO)YR^(B), —NR^(A)(CO)YR^(B), —S(CO)YR^(B), —NR^(A)C(═S)YR^(B),—OC(═S)YR^(B), —C(═S)YR^(B), —YC(═NR^(A))YR^(B), —YC(═N—OR^(A))YR^(B),—YC(═N—NR^(A)R^(B))YR^(B), —COCOR^(B), —COMCOR^(B) (where M is a C₁₋₆alkyl group), —YP(O)(YR^(C))(YR^(C)), —P(O)(R^(C))₂, —Si(R^(C))₃,—NR^(A)SO₂R^(B), and —NR^(A)SO₂NR^(A)R^(B), wherein each occurrence of Yis, independently, —O—, —S—, —NR^(A)—, or a chemical bond (i.e.,—(CO)YR^(B) thus encompasses —C(═O)R^(B), —C(═O)OR^(B), and—C(═O)NR^(A)R^(B)).

R^(C) is selected from alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and heterocyclyl. At eachoccurrence, each of R^(A) and R^(B) is, independently, selected fromhydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,cycloalkynyl, aryl, heteroaryl, and heterocyclyl.

Each of R^(A), R^(B) and R^(C) optionally bears one or more substituentsselected from amino, alkylamino, dialkylamino, aminocarbonyl, halogen,alkyl, aryl, heteroalkyl, heteroaryl, carbocycle, heterocycle,alkylaminocarbonyl, dial kylaminocarbonyl, alkylaminocarbonyloxy,dialkylaminocarbonyloxy, nitro, cyano, carboxy, alkoxycarbonyl,alkylcarbonyl, alkoxy, haloalkoxy groups, hydroxy, protected hydroxylgroups (e.g., —O—X, where X is acyl, phenyl, substituted phenyl, benzyl,substituted benzyl, phenethyl, or substituted phenethyl), -M-heteroaryl,-M-heterocycle, -M-aryl, -M-OR^(B), -M-SR^(B), -M-NR^(A)R^(B),-M-OC(O)NR^(A)R^(B), -M-C(═NR^(B))NR^(A)R^(B), -M-C(═NR^(A))OR^(B),-M-P(═O)(R^(C))2, Si(R^(C))₃, -M-NR^(A)C(O)R^(B), -M-NR^(A)C(O)OR^(B),-M-C(O)R^(B), -M-C(═S)R^(B), -M-C(═S)NR^(A)R^(B), -M-C(O)NR^(A)R^(B),-M-C(O)NR^(B)-M-NR^(A)R^(B), -M-NR^(B)C(NR^(A))NR^(A)R^(B),-M-NR^(A)C(S)NR^(A)R^(B), -M-S(O)₂R^(A), -M-C(O) R^(A), -M-OC(O) R^(A),-MC(O)SR^(B), -M-S(O)₂NR^(A)R^(B), —C(O)-M-C(O)R^(B), -MCO₂RB,-MC(═O)NR^(A)R^(B), -M-C(═NH)NR^(A)R^(B), and -M-OC(═NH)NR^(A)R^(B),wherein M is a C₁₋₆ alkyl group. Non-limiting illustrations of asubstituted R^(A), R^(B) or R^(C) group include haloalkyl andtrihaloalkyl, alkoxyalkyl, halophenyl, chloromethyl, trichloromethyl,trifluoromethyl, methoxyethyl, alkoxyphenyl, halophenyl, —CH₂-aryl,—CH₂-heterocycle, —CH₂C(O)NH₂, —C(O)CH₂N(CH₃)₂, —CH₂CH₂OH, —CH₂OC(O)NH₂,—CH₂CH₂NH₂, —CH₂CH₂CH₂NEt₂, —CH₂OCH₃, —C(O)NH₂, —CH₂CH₂-heterocycle,—C(═S)CH₃, —C(═S)NH₂, —C(═NH)NH₂, —C(═NH)OEt, —C(O)NH-cyclopropyl,—C(O)NHCH₂CH₂-heterocycle, —C(O)NHCH₂CH₂OCH₃, —C(O)CH₂CH₂NHCH₃,—CH₂CH₂F, —C(O)CH₂-heterocycle, —CH₂C(O)NHCH₃, —CH₂CH₂P(═O)(CH₃)₂, and—Si(CH₃)₃.

An alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, heteroalkyl, cycloalkyl,cycloalkenyl, cycloalkynyl, or heterocyclic group may contain one ormore substituents selected from those listed above for aryl andheteroaryl groups, in addition to ═O, ═S, ═NH, ═NNR^(A)R^(B),═NNHC(O)R^(B), ═NNHCO₂RB, or ═NNHSO₂RB, wherein R^(A) and R^(B) are asdefined above.

In drawings of chemical structures in this document, atoms not indicatedby label or line are understood to be H.

Other features and advantages of the invention will be apparent from thefollowing detailed description and the claims.

EGFR Mutants

The EGFR-driven cancers which can be treated using the compositions andmethod of the invention include, for example, EGFR mutants including oneor more deletions, substitutions, or additions in the amino acid ornucleotide sequences of EGFR, or fragments thereof.

Mutations in EGFR can occur in any part of the EGFR sequence. Generally,EGFR mutants arise from mutations in the kinase domain (i.e., exons18-24 in the EGFR sequence) or in the extracellular domain (i.e., exons2-16 in the EGFR sequence). For example, mutations typically occur inthe kinase domain, including one or more of a point mutation in exon 18(e.g., L688P, V689M, P694L/S, N700D, L703V, E709K/Q/A/GN, 1715S, L718P,G719C/A/S/R, or S720P/F), a deletion in exon 19 that may or may notinclude an insertion (e.g., delG719, delE746_E749, delE746_A750,delE746_A750insRP, delE746_A750insQP, delE746_T751,delE746_T751insA/I/V, delE746_T751insVA, delE746_S752,delE746_S752insAN/D, delE746_P53insLS, delL747_E749, delL747_A750,delL747_A750insP, delL747_T751, delL747_T751 insP/S/Q, delL747_T751insPI, delL747_S752, delL747_S752insQ, delL747_P753, delL747_P753insS/Q,delL747_L754insSR, delE749_A750, delE749_A750insRP, delE749_T751,delT751_(—)1759, delT751_(—)1759insS/N, or delS752_(—)1759), aduplication in exon 19 (e.g., K739_(—)144dupKIPVAI), a point mutation inexon 19 (e.g., L730F, W731Stop, P733L, G735S, V742A, E746V/K, A750P,T7511, S752Y, P753S, A754P, or D761Y), an in-frame insertion in exon 20(e.g., D761_E762insEAFQ, A767_S768insTLA, V769_D770insY, V769_D770insCV,V769_D770insASV, D770_N771insD/G, D770_N771insNPG, D770_N771insSVQ,P772_H773insNN, P772_H773insYNP, or V774_C775insHV), a deletion in exon20 that may or may not include an insertion (e.g., delM766_A767,delM766_A767insAI, delA767_V769, delD770, or delP772_H773insNP), aduplication in exon 20 (e.g., S768_D770dupSVD, A767_V769dupASV, orH773dupH), a point mutation in exon 20 (e.g., D761N, A763V, V765A/M,S7681, V769L/M, S7681, P772R, N771T, H773R/Y/L, V774M, R776G/H/C,G779S/F, T783A, T784F, L792P, L798H/F, T790M, R803W, K806E, or L814P),or a point mutation in exon 21 (e.g., G810S, N826S, L833V, H835L, L838V,A839T, K846R, T8471, H850N, V8511/A, 1853T, L858M/R, A859T, L861Q/R,G863D, A864T, E866K, or G873E). In lung cancer, activation mutants aretypical, and 90% deletion of 746-750 (ELREA) and L858R result insustained phosphorylation of EGFR without ligand stimulation. Inparticular, drug resistance in 50% of lung cancers arises from the T790Mpoint mutation.

For example, in glioblastoma, mutations typically, but not exclusively,occur in the extracellular domain, including EGFR variant I (EGFRvI)lacking the extracellular domain and resembling the v-erbB oncoprotein;EGFRvII lacking 83 amino acids from domain IV; and EGFRvIII lackingamino acids 30-297 from domains I and II, which is the most commonamplification and is reported in 30-50% of glioblastomas and 5% ofsquamous cell carcinoma. Other mutations for glioblastoma include one ormore of point mutations in exon 2 (e.g., D46N or G63R), exon 3 (e.g.,R108K in domain I), exon 7 (e.g., T263P or A289D/TN in domain II), exon8 (e.g., R324L or E330K), exon 15 (e.g., P596L or G598V in domain IV),or exon 21 (L861Q in the kinase domain).

EGFR mutants also include those with a combination of two or moremutations, as described herein. Exemplary combinations include S7681 andG719A; S7681 and V769L; H773R and W731Stop; R776G and L858R; R776H andL861Q; T790M and L858R; T790M and delE746_A750; R803W anddelE746_T751insVA; delL747_E749 and A750P; delL747_S752 and E746V;delL747_S752 and P753S; P772_H773insYNP and H773Y; P772_H773insNP andH773Y; and D770_N771insG and N771T. Other exemplary combinations includeany including T790M (e.g., T790M and L858R or T790M and delE746_A750,with or without concomitant inhibition of single mutants L858R anddelE746_A750).

EGFR mutants can be either activation mutants or resistant mutants.Activation mutants include those with substitutions that increase drugsensitivity (e.g., G719C/S/A, delE746_A750, or L858R). Resistant mutantsinclude those with substitutions that increase drug resistance (e.g.,T790M or any combination including T790M).

EGFR-driven cancers include those having any mutant described herein.For example, EGFRvIII is commonly found in glioblastoma and has alsobeen reported in breast, ovarian, prostate, and lung carcinomas.Exemplary EGFR-driven cancers: glioblastoma, lung cancer (e.g., squamouscell carcinoma, non-small cell lung cancer, adenocarcinoma,bronchioloalveolar carcinoma (BAC), BAC with focal invasion,adenocarcinoma with BAC features, and large cell carcinoma), pancreaticcancer, head and neck cancers (e.g., squamous cell carcinoma), breastcancer, colorectal cancer, epithelial cancer (e.g., squamous cellcarcinoma), ovarian cancer, and prostate cancer.

In particular, the invention described herein would benefit patientpopulations having higher risk for TKI-resistant mutations. About 8,000to 16,000 new cases per year can be estimated based on: incidence ofnon-small cell lung cancer (about 160,000 new cases in the U.S.), theresponse to erlonitinib in the general population (about 10%, resultingin a sensitive population of 16,000), the presence of activationmutations (10-20% in white and 30-40% in Asian population, resulting ina sensitive population of 16,000-32,000), acquisition of secondaryresistance (most if not all patients, resulting in a sensitivepopulation of 16,000-32,000), and percentage of patients carrying theT790M point mutations (about 50%, resulting in a sensitive population of8,000-16,000). Patients having TKI-resistant mutations include thosepatients having cancers resistant to one or more of erlotinib,gefitinib, CL-387,785, BIBW 2992 (CAS Reg. No. 439081-18-2), Cl-1033,neratinib (HKI-272), MP-412 (AV-412), PF-299804, AEE78, and XL64.

In particular, the inventions relates to treatment of EGFR-drivencancers having the T790M point mutation. Generally, reversibleinhibitors (e.g., C1-1033, neratinib (HKI-272), and PF-299804) are lesspotent in cell lines having the T790M mutation and do not inhibit T790Mat clinically achievable concentrations. Since the ATP Km of T790M andWT are similar, concentrations that inhibit the mutant will inhibit theWT and result in gastrointestinal and cutaneous events.

An EGFR mutant also includes other amino acid and nucleotide sequencesof EGFR with one or more deletions, substitutions, or additions, such aspoint mutations, that retain or increase tyrosine kinase orphosphorylation activity. Where the mutant is a protein or polypeptide,preferable substitutions are conservative substitutions, which aresubstitutions between amino acids similar in properties such asstructural, electric, polar, or hydrophobic properties. For example, thesubstitution can be conducted between basic amino acids (e.g., Lys, Arg,and His), or between acidic amino acids (e.g., Asp and Glu), or betweenamino acids having non-charged polar side chains (e.g., Gly, Asn, Gin,Ser, Thr, Tyr, and Cys), or between amino acids having hydrophobic sidechains (e.g., Ala, Val, Leu, Ile, Pro, Phe, and Met), or between aminoacids having branched side chains (e.g., Thr, Val, Leu, and Ile), orbetween amino acids having aromatic side chains (e.g., Tyr, Trp, Phe,and His).

Where the mutant is a nucleic acid, the DNA encoding an EGFR mutantprotein may comprise a nucleotide sequence capable of hybridizing to acomplement sequence of the nucleotide sequence encoding an EGFR mutant,as defined herein, under stringent conditions. As used herein, thestringent conditions include low, medium or high stringent conditions.An example of the stringent conditions includes hybridization atapproximately 42-55° C. in approximately 2-6×SSC, followed by wash atapproximately 50-65° C. in approximately 0.1-1×SSC containingapproximately 0.1-0.2% SDS, where 1×SSC is a solution containing 0.15 MNaCl and 0.015 M Na citrate, pH 7.0. Wash can be performed once or more.In general, stringent conditions may be set at a temperatureapproximately 5° C. lower than a melting temperature (Tm) of a specificnucleotide sequence at defined ionic strength and pH.

The amino acid and nucleotide sequences of EGFR and DNAs encoding themare available from known databases such as NCBI GenBank (USA), EMBL(Europe), etc. For example, GenBank accession numbers for EGFR [Homosapiens] include MIM131550, AA128420, NM_(—)005228, NP_(—)005219.2, andGeneID: 1956.

Characterization of EGFR-Driven Cancers

The compositions and methods of the invention can be used to treatsubjects having an EGFR-driven cancer (i.e., cancers characterized byEGFR mutant expression or overexpression). EGFR mutant expression oroverexpression can be determined in a diagnostic or prognostic assay byevaluating levels of EGFR mutants in biological sample, or secreted bythe cell (e.g., via an immunohistochemistry assay using anti-EGFRantibodies or anti-p-EGFR antibodies; FACS analysis, etc.).Alternatively, or additionally, one can measure levels of EGFRmutant-encoding nucleic acid or mRNA in the cell, e.g., via fluorescentin situ hybridization using a nucleic acid based probe corresponding toan EGFR mutant-encoding nucleic acid or the complement thereof; (FISH;see WO98/45479, published October, 1998), Southern blotting, Northernblotting, or polymerase chain reaction (PCR) techniques, such as realtime quantitative PCR (RT-PCR). One can also study EGFR mutantexpression by measuring shed antigen in a biological sample, such asserum, e.g., using antibody-based assays (see also, e.g., U.S. Pat. No.4,933,294, issued Jun. 12, 1990; WO91/05264, published Apr. 18, 1991;U.S. Pat. No. 5,401,638, issued Mar. 28, 1995; and Sias et al., J.Immunol. Methods 132:73 (1990)). Aside from the above assays, various invivo assays are available to the skilled practitioner. For example, onecan expose cells within the body of the mammal to an antibody which isoptionally labeled with a detectable label, e.g., a radioactive isotope,and binding of the antibody to cells in the mammal can be evaluated,e.g., by external scanning for radioactivity or by analyzing a biopsytaken from a mammal previously exposed to the antibody.

Examples of biological properties that can be measured in isolated cellsinclude mRNA expression, protein expression, and DNA quantification.Additionally, the DNA of cells isolated by the methods of the inventioncan be sequenced, or certain sequence characteristics (e.g.,polymorphisms and chromosomal abnormalities) can be identified usingstandard techniques, e.g., FISH or PCR. The chemical components ofcells, and other analytes, may also be assayed after isolation. Cellsmay also be assayed without lysis, e.g., using extracellular orintracellular stains or by other observation, e.g., morphology or growthcharacteristics in various media.

While any hybridization technique can be used to detect the generearrangements, one preferred technique is fluorescent in situhybridization (FISH). FISH is a cytogenetic technique which can be usedto detect and localize the presence or absence of specific DNA or RNAsequences on chromosomes. FISH incorporates the use of fluorescentlylabeled nucleic acid probes which bind only to those parts of thechromosome with which they show a high degree of sequence similarity.

Fluorescence microscopy can be used to find out where the fluorescentprobe bound to the chromosome. The basic steps of FISH are outlinedbelow. Exemplary FISH probes include Vysis EGFR SpectrumOrangel CEPSpectrumGreen Probe (Abbott, Downers Grove, Ill.), which hybridizes toband 7p12; and ZytoLight SPEC EGFR/CEN 7 Dual Color Probe (ZytoVision),which hybridizes to the alpha-satellite sequences of the centromere ofchromosome 7.

For FISH, a probe is constructed that is long enough to hybridizespecifically to its target (and not to similar sequences in the genome),but not too large to impede the hybridization process. Probes aregenerally labeled with fluorophores, with targets for antibodies, withbiotin, or any combination thereof. This can be done in various ways,for example using random priming, nick translation, and PCR using taggednucleotides.

Generally, a sample or aliquot of a population of cells is used for FISHanalysis. For example, in one method of preparation, cells aretrypsinized to disperse into single cells, cytospun onto glass slides,and then fixed with paraformaldehyde before storing in 70% ethanol. Forpreparation of the chromosomes for FISH, the chromosomes are firmlyattached to a substrate, usually glass. After preparation, the probe isapplied to the chromosome RNA and starts to hybridize. In several washsteps, all unhybridized or partially hybridized probes are washed away.If signal amplification is necessary to exceed the detection thresholdof the microscope (which depends on many factors such as probe labelingefficiency, the kind of probe, and the fluorescent dye), fluorescenttagged antibodies or strepavidin are bound to the tag molecules, thusamplifying the fluorescence.

An epifluorescence microscope can be used for observation of thehybridized sequences. The white light of the source lamp is filtered sothat only the relevant wavelengths for excitation of the fluorescentmolecules arrive onto the sample. Emission of the fluorochromes happens,in general, at larger wavelengths, which allows one to distinguishbetween excitation and emission light by mean of another optical filter.With a more sophisticated filter set, it is possible to distinguishbetween several excitation and emission bands, and thus between severalfluorochromes, which allows observation of many different probes on thesame strand.

Depending on the probes used, FISH can have resolution ranging from hugechromosomes or tiny (˜100 kilobase) sequences. The probes can bequantified simply by counting dots or comparing color.

Allele-specific quantitative real time-PCR may also be used to identifya nucleic acid encoding a mutant EGFR protein (see, for e.g., DiagnosticInnovations DxS BCR-ABL T3151 Mutation Test Kit, and Singer et al.,Methods in Molec. Biol. 181:145 (2001)). This technique utilizes Taq DNApolymerase, which is extremely effective at distinguishing between amatch and a mismatch at the 3′-end of the primer (when the 3′-base ismismatched, no efficient amplification occurs). Using this technique,the 3′-end of the primer may be designed to specifically hybridize to anucleic acid sequence that corresponds to a codon that encodes a mutantamino acid in an EGFR mutant, as described herein. In this way, thespecific mutated sequences can be selectively amplified in a patientsample. This technique further utilizes a Scorpion probe molecule, whichis a bifunctional molecule containing a PCR primer, a fluorophore, and aquencher. The fluorophore in the probe interacts with a quencher, whichreduces fluorescence. During a PCR reaction, when the Scorpion probebinds to the amplicon, the fluorophore and quencher in the Scorpionprobe become separated, which leads to an increase in fluorescence fromthe reaction tube. Any of the primers described herein may be used inallele-specific quantitative real time PCR.

A biological sample can be analyzed to detect a mutation in an EGFRgene, or expression levels of an EGFR gene, by methods that are known inthe art. For example, methods such as direct nucleic acid sequencing,altered hybridization, aberrant electrophoretic gel migration, bindingor cleavage mediated by mismatch binding proteins, single-strandconformational polymorphism (SSCP) analysis, or restriction fragmentlength polymorphism (RFLP) analysis of PCR products derived from apatient sample can be used to detect a mutation in an EGFR gene; ELISAcan be used to measure levels of EGFR polypeptide; and PCR can be usedto measure the level of an EGFR nucleic acid molecule.

Any of these techniques may be used to facilitate detection of amutation in a candidate gene, and each is well known in the art;examples of particular techniques are described, without limitation, inOrita et al. (Proc. Natl. Acad. Sci. USA 86:2766 (1989)) and Sheffieldet al. (Proc. Natl. Acad. Sci. USA 86:232 (1989)). Furthermore,expression of the candidate gene in a biological sample (e.g., a biopsy)may be monitored by standard Northern blot analysis or may be aided byPCR (see, e.g., Ausubel et al., Current Protocols in Molecular Biology,John Wiley & Sons, New York, N.Y. (1995); PCR Technology: Principles andApplications for DNA Amplification, H. A. Ehrlich, Ed., Stockton Press,NY; Yap et al., Nucl. Acids. Res. 19:4294 (1991)).

One skilled in the art may identify in a nucleic acid or proteinsequence a residue (e.g., amino acid or nucleotide) or codon thatcorresponds to a residue or codon in wild-type EGFR or EGFR mutantsusing a number of sequence alignment software programs (e.g., NCBI BLASTwebsite). Such software programs may allow for gaps in the alignment ofthe compared sequences. Using such software, one skilled in the art mayidentify a nucleotide, amino acid, or amino acid that corresponding to aspecific nucleotide, amino acid, or codon in wild-type EGFR or EGFRmutants.

Levels of EGFR expression (e.g., DNA, mRNA, or protein) in a biologicalsample can be determined by using any of a number of standard techniquesthat are well known in the art or described herein. Exemplary biologicalsamples include plasma, blood, sputum, pleural effusion, bronchoalveolarlavage, or biopsy, such as a lung biopsy and lymph node biopsy. Forexample, EGFR expression in a biological sample (e.g., a blood or tissuesample) from a patient can be monitored by standard northern blotanalysis or by quantitative PCR (see, e.g., Ausubel et al., supra; PCRTechnology: Principles and Applications for DNA Amplification, H. A.Ehrlich, Ed., Stockton Press, NY; Yap et al., Nucl. Acids. Res. 19:4294(1991)).

Synthesis

Compounds of Formula (I) can be prepared using methods and materialsanalogous to those described in the art, e.g., as disclosed in detail inInternational patent applications WO 2004/080980, WO 2005/016894, WO2006/021454, WO 2006/021457, WO 2009/143389, and WO 2009/126515. Forinstance, compounds of Formula (I) in which R^(e) is H and R^(d) is H,Cl, CF₃, or CH₃, can be synthesized from 2,4-dichloropyrimidine,2,4,5-trichloropyrimidine, 2,4-dichloro-5-(trifluoromethyl)pyrimidine,or 2,4-dichloro-5-methylpyrimidine, respectively, as described in PCTPublication No. WO/2009/143389.

Compounds of Formula (I) in which R^(d) and R^(e), together with thepyrimidine ring atoms to which they are attached, form a 5- or6-membered ring containing one or two heteroatoms can be synthesized asdescribed in PCT Publication No. WO2009/126515.

Compounds of Formula (I) in which U¹ and U² are N can be synthesized,for example, using methods analogous to those described in Scheme A1.

Compounds of Formula (I) in which U³ is N, one of U¹ and U² is N, andthe other is C—R^(d) can be synthesized, for example, using methodsanalogous to those described in Scheme A2.

Further details are provided in the Examples.

Formulation

Compounds of Formula I can be Formulated into a pharmaceuticalcomposition that comprises a compound of Formula I (as an activepharmaceutical ingredient) or a pharmaceutically acceptable salt thereofand a pharmaceutically acceptable excipient. As such, the presentdisclosure provides a pharmaceutical composition comprising a compoundof Formula I or a pharmaceutically acceptable salt thereof and apharmaceutically acceptable excipient.

Pharmaceutically acceptable compositions containing a compound ofFormula I suitable for administration may be Formulated usingconventional materials and methods, a wide variety of which are wellknown. Suitable dosage forms include those in solution, suspension oremulsion form, and solid oral dosage forms such as capsules, tablets,gel caps, caplets, etc. Methods well known in the art for makingFormulations, including the foregoing unit dosage forms, are found, forexample, in “Remington: The Science and Practice of Pharmacy” (20th ed.,ed. A. R. Gennaro, 2000, Lippincott Williams & Wilkins).

Compounds of Formula (I) can be Formulated for any route ofadministration (e.g., orally, rectally, parenterally, intracisternally,intravaginally, intraperitoneally, topically (as by transdermal patch,powders, ointments, or drops), sublingually, bucally, as an oral ornasal spray) effective for use in the methods of the invention. For usein the methods of the invention, compounds of Formula (I) are preferablyFormulated in dosage unit form for ease of administration and uniformityof dosage. For example, a compound of Formula (I) can be Formulated foras a capsule for oral administration containing nominally 10 mg, 50 mg,100 mg, 150 mg, 250 mg, 500 mg, or any dosage amounts described hereinas the free base or acid addition salt of the compound (e.g., thehydrochloride salt). The unit dosage forms of the invention can includea compound of the invention, or a salt thereof, Formulated withexcipients, fillers, flow enhancers, lubricants, and/or disintegrants asneeded. For example, a unit dosage form can include colloidal silicondioxide (a flow enhancer), lactose anhydrous (a filler), magnesiumstearate (a lubricant), microcrystalline cellulose (a filler), and/orsodium starch glycolate (a disintegrant). The compound of the inventionand the inactive ingredients can be Formulated utilizing, for example,conventional blending, and encapsulation processes. Alternatively,compounds of Formula (I) are Formulated as described in PCT PublicationNos. WO2009/143389 and WO2009/126515.

Therapy

Compounds of Formula (I) can be useful for treating EGFR-driven cancers.In particular, the compounds can be useful for treating EGFR-drivencancers that express EGFR mutants and for treating EGFR-driven cancersthat are refractory to TKI therapies (e.g., erlotinib or gefitinib).

Such cancers can include, among others, non-small cell lung cancer(NSCLS), including one or more of squamous cell carcinoma,adenocarcinoma, adenocarcinoma, bronchioloalveolar carcinoma (BAC), BACwith focal invasion, adenocarcinoma with BAC features, and large cellcarcinoma; neural tumors, such as glioblastomas; pancreatic cancer; headand neck cancers (e.g., squamous cell carcinoma); breast cancer;colorectal cancer; epithelial cancer, including squamous cell carcinoma;ovarian cancer; prostate cancer; adenocarcinomas; and including cancerswhich are EGFR mediated.

The present invention is based upon the discovery that compounds ofFormula (I) can be used to treat EGFR-driven cancers, EGFR-drivencancers that express EGFR mutants, and for treating EGFR-driven cancersthat are refractory to TKI therapy, such as erlotinib or gefitinib.Compounds of Formula (I) can also be used in a maintenance role toprevent recurrence of cancer in patients in need of such a treatment.

The effective systemic dose of a compound of Formula (I) will typicallybe in the range of an average daily dose of from 10 mg to 2,000 mg ofthe compound per kg of patient body weight, administered in single ormultiple doses. Generally, a compound of the invention may beadministered to patients in need of such treatment in a daily dose rangeof about 50 to about 2,000 mg per patient. Administration may be once ormultiple times daily, weekly (or at some other multiple-day interval) oron an intermittent schedule. For example, the compound may beadministered one or more times per day on a weekly basis (e.g. everyMonday) indefinitely or for a period of weeks, e.g. 4-10 weeks.Alternatively, it may be administered daily for a period of days (e.g.2-10 days) followed by a period of days (e.g. 1-30 days) withoutadministration of the compound, with that cycle repeated indefinitely orfor a given number of repetitions, e.g. 4-10 cycles. As an example, acompound of the invention may be administered daily for 5 days, thendiscontinued for 9 days, then administered daily for another 5 dayperiod, then discontinued for 9 days, and so on, repeating the cycleindefinitely, or for a total of 4-10 times.

When a TKI (e.g., erlotinib or gefitinib) is used in combination with acompound of Formula (I), each component of the combination therapy maybe administered at their monotherapy dosing levels and schedules. Forexample, erlotinib has been administered orally for the treatment ofNSCLC at 150 mg daily and of pancreatic cancer at 100 mg daily. Inanother example, gefitinib has been administered orally for thetreatment of NSCLC at 250 mg daily.

The effective systemic dose of a compound of the invention willtypically be in the range of an average daily dose of from 10 mg to2,000 mg of the compound per kg of patient body weight, administered insingle or multiple doses. Generally, a compound of the invention may beadministered to patients in need of such treatment in a daily dose rangeof about 50 to about 2,000 mg per patient. Administration may be once ormultiple times daily, weekly (or at some other multiple-day interval) oron an intermittent schedule. For example, the compound may beadministered one or more times per day on a weekly basis (e.g. everyMonday) indefinitely or for a period of weeks, e.g. 4-10 weeks.Alternatively, it may be administered daily for a period of days (e.g.2-10 days) followed by a period of days (e.g. 1-30 days) withoutadministration of the compound, with that cycle repeated indefinitely orfor a given number of repititions, e.g. 4-10 cycles. As an example, acompound of the invention may be administered daily for 5 days, thendiscontinued for 9 days, then administered daily for another 5 dayperiod, then discontinued for 9 days, and so on, repeating the cycleindefinitely, or for a total of 4-10 times.

Alternatively, a TKI (e.g., erlotinib or gefitinib) is used incombination with a compound of Formula (I) with a reduced dosing levelin one or both components.

The following examples are put forth so as to provide those of ordinaryskill in the art with a complete disclosure and description of how themethods and compounds claimed herein are performed, made, and evaluated,and are intended to be purely exemplary of the invention and are notintended to limit the scope of what the inventors regard as theirinvention.

Step 1: Synthesis of Compound 1

To a solution of 2-iodoaniline (1.0 eq) and dimethylphosphine oxide (1.1eq) in DMF were added potassium phosphate (1.1 eq) and palladiumacetate/Xantphos (catalytic). The reaction was stirred at 150° C. for 3hours and cooled to room temperature. The solvent was evaporated and theresidue was worked up with DCM/water. The crude product was purifiedwith a column (EtOAc/MeOH 10:1) to give 1 as a brown solid (80% yield).

Step 2: Synthesis of 2:

2,4,5-Trichloropyrimidine (1.57 eq), 1 (1.0 eq), and potassium carbonate(3.14 eq) in DMF were stirred at 60° C. for 5 hours and then cooled toroom temperature. The mixture was filtered and the filtrate wasconcentrated. The residue was purified by column chromatography (ISCOmachine) (DCM/MeOH 20:1) to give 2 as a yellow solid (61% yield).

Step 2a: Synthesis of 8 and 3:

A suspension of 10 g (59.5 mmol, 1.0 eq) of 4-methoxy-3-nitroaniline in65 mL of dioxane and 65 mL of water was adjusted to pH 12 with 40% NaOH,and then Boc₂O (26 g, 119.1 mmol, 2.0 eq) was added in 3 portions underice bath. The reaction was stirred at room temperature overnight. Afterstanding, the mixture was filtered to give a yellow solid, 15 g, in 95%yield.

Compound 8 (6 g, 22.4 mmol) was dissolved in 55 mL of ethyl acetate andPd/C (10%, wet, 0.5 g) was added. The reduction was shaken at roomtemperature under H₂ (30 psi) for 1 hr and filtered. The filtrate wasevaporated to a tan solid, 5.4 g, in a quantitative yield.

Step 3: Synthesis of 4:

A suspension of 2(1.27 g, 4.0 mmol), 3-Boc-amino-5-methoxyaniline (965mg, 4.0 mmol), palladium acetate (133 mg, 0.59 mmol), XantPhos (352 mg,0.61 mmol) and potassium phosphate (1.4 g, 6.6 mmol) in anhydrous DMF(35 mL) was heated at 120° C. overnight. After the reaction was coolingto room temperature, ethyl acetate was added to dilute the reaction andthe content was filtered through celite. Solvent was removed undervacuum. The residue was purified by flash column chromatography onsilica gel to give pure product 1.3 g (yield 62%) as a tan solid.

Step 4: Synthesis of 5:

HCl/dioxane (4N, 4 mL) was added to a solution of compound 4 (440 mg,0.85 mmol) in MeOH (4 mL). The reaction mixture was stirred at room tempovernight. White precipitate was filtered and dried to give the titleproduct as a white solid (339 mg, Yield 81%).

Step 5: Synthesis of 6:

Compound 5 (100 mg, 0.15 mmol) was dissolved in CH₂Cl₂ (1.6 mL) and DIEA(174 μL, 1 mmol). The solution was cooled in an ice bath. Aryloylchloride (13ul, 0.165 mmol) was added dropwise. The content was stirredat room temp for an hour. Solvent was removed in vacuo and the residuewas purified by a prep-TLC plate (7.5% MeOH/DCM) to give final productas a tan solid (24 mg, yield 34%).

Step 1: Synthesis of 10:

Compound 2 (2 g, 6.3 mmol) was dissolved in NH₃/MeOH (7N, 20 mL) in asealed tube and the content was heated at 100° C. for 3 days. Thevolatile was evaporated and the residue partitioned between EtOAc/H20,the organic layer was separated and aqueous was extracted withEtOAc(2×). Combined organic dried(Na₂SO₄). After concentration, theresidue was column purified on Silica gel(10% MeOH/DCM) to give theproduct as a white solid(1.1 g, yield 57%).

Step 2: Synthesis of 11

Compound 10(908 mg, 3.0 mmol) and 2-iodo-4-nitroanisole (963 mg, 4.15mmol) were dissolved in 25 mL anhydrous DMF in a sealed tube and wasadded Pd(OAc)₂ (86 mg, 0.38 mmol), XantPhos (227 mg, 0.30 mmol), K₃PO₄(921 mg, 4.3 mmol). The content was heated at 120° C. overnight. Aftercooling to the room temp, EtOAc was added and the mixture was filteredthrough celite, washed with more EtOAc. Combined filtrate was conc invacuo, and the residue was purified by CombiFlash(MeOH/DCM). The product(476 mg, 35.5%) was obtained as a tan solid.

Step 3: Synthesis of 12

Compound 11 (476 mg, 1.1 mmol) was dissolved in THF (18 mL)/H₂O (13 mL)and was added Fe(300 mg) and NH₄Cl(300 mL). The mixture was heated at65° C. overnight. The liquid was decanted and the solid residue waswashed with more THF. Combined solution was conc to give a residue. Theresidue was dissolved in DCM and filtered through cotton. The solutionagain is conc to give crude product 480 mg.

Step 4: Synthesis of 14

Compound 12 (125.4 mg, 0.3 mmol), 4-bromocrotonoic acid (49 mg, 0.3mmol) was dissolved in 3 mL dry DCM. EDCl(63 mg, 0.33 mmol) was thenadded. The mixture was stirred at room temperature for 2 hrs. Volatileswere removed in vacuo and THF (3 mL) was added, followed bydimethylamine/H₂O solution (40%, 0.5 mL, 4.0 mmol). The mixture wasstirred at room temperature for another 2 hrs. Solvent was removed invacuo and the residue was purified by prep-TLC (10% MeOH/DCM) to givethe final product as a tan solid(48 mg, yield 30.2%).

General procedures: compound 5 (100 mg, 0.15 mmol) was dissolved inCH₂Cl₂ (1.6 mL) at 0° C. and DIEA (174 μL, 1 mmol) was added. Acidchloride (13 μl, 0.165 mmol, 1.1 eq) was added dropwise. The content wasstirred at room temp for an hour. Solvent was removed in vacuo and theresidue was purified by a prep-TLC plate(10% MeOH/DCM), thecorresponding bands were collected to give final products.

General procedures: compound 12 (84 mg, 0.20 mmol), respective acid(0.27 mmol, 1.35 eq.) were dissolved in dry DMF (2.0 mL). DCC (56 mg,0.27 mmol, 1.35 eq) was added. The content was stirred at room tempovernight. Solvent was removed in vacuo and the residue was purified bya prep-TLC plate (6.5% MeOH/DCM), the corresponding bands were collectedto give final products.

Compound 12 (200 mg, 0.48 mmol), and NEt₃ (344 μL) was dissolved in 5 mLTHF at room temperature, 2-chloroethylenesulfonyl chloride (115 μL, 1.1mmol) was added and the content was stirred at room temperature for 1hr. The volatile was removed in vacuo and the residue was purified onprep-TLC (2×) (7.5% MeOH/DCM). The product was a tan solid (56 mg, yield23%).

Step 1: Synthesis of 17

Compound 2 (158 mg, 0.50 mmol), 1,3-diaminocyclohexane (57.1 mg, 0.5mmol) was dissolved in methoxyethanol (1.6 mL) in a sealed tube andHCl/EtOH (200 μl) was added. The content was heated at 110° C.overnight. Solvent was removed in vacuo and the residue was purified by2 prep-TLC plate (360 mL DCM/24 mL MeOH/12 mL 7N NH₃.MeOH) to give finalproduct as a light colored solid (134 mg, yield 68%).

Step 2: Synthesis of 18

Compound 17 (70 mg, 0.177 mmol) was dissolved in CH₂Cl₂ (1.6 mL) at 0°C. and DIEA (174 μL, 1 mmol) was added. Aryloyl chloride (15 μl, 0.185mmol) was added dropwise. The content was stirred at room temp for anhour. Solvent was removed in vacuo and the residue was purified by aprep-TLC plate (10% MeOH/DCM) to give two final product as tan solids(trans 29.4 mg, yield 43.8%; cis 14.1 mg, 21.4%).

Step 1: Synthesis of 21

Compound 19 (154 mg, 0.54 mmol) and compound 20 (107 mg, 0.54 mmol) weredissolved in 4 mL anhydrous DMF in a sealed tube and was added Pd(OAc)₂(14 mg, 0.062 mmol), XantPhos (37 mg, 0.064 mmol), and K₃PO₄ (150 mg,0.71 mmol). The content was heated at 120° C. overnight. After coolingto the room temp, EtOAc was added and the mixture was filtered throughcelite, washed with more EtOAc. Combined filtrate was conc in vacuo, andthe residue was purified by CombiFlash (MeOH/DCM). The product 21 (140mg, yield 58%) was obtained as an orange solid.

Step 2: Synthesis of 22

Compound 21 (140 mg, 0.31 mmol) was dissolved in THF/water (3 mL/3 mL)mixture and Fe (75 mg,), NH₄Cl (75 mg) was added. The content was heatedat 65° C. overnight. After cooling to room temp., the mixture wasfiltered through cotton. The filtrate was concentrated and the residuewas dissolved in 7.5% MeOH/DCM and was filtered through cotton again.After solvent was removed in vacuo, the crude product was obtained as atan solid (126 mg, yield 96%).

Step 3: Synthesis of 23

Compound 22 (163 mg, 0.15 mmol) was dissolved in CH₂Cl₂(1.6 mL) at 0° C.and DIEA (174 μL, 1 mmol) was added. Aryloyl chloride (13 μl, 0.165mmol) was added dropwise. The content was stirred at room temp for anhour. Solvent was removed in vacuo and the residue was purified by aprep-TLC plate (7.5% MeOH/DCM) to give final product as a tan solid (40mg, yield 56%).

Procedure: compound 24 (49 mg, 0.1 mmol) was dissolved in 0.75 mL HCOOHand H₂O₂ (37%, 0.4 mL) was added. The content was heated at 40° C. for 1hr. The volatiles were removed by N₂ blow and the residue was purifiedby prep-TLC (7.5% MeOH/DCM) to give the product as a tan solid (13.7 mg,yield 27%).

Step 1: Synthesis of 26

A suspension of 5-bromo-2,4-dichloropyrimidine (2. g, 12.3 mmol, 1.0eq), 2-dimethylphosphonylbenzeneamine (2.08 g, 12.3 mmol, 1.0 eq), K₂CO₃(2.04 g, 14.8 mmol, 1.2 eq), and nBu₄HSO₄ (417 mg, 1.23 mmol, 0.1 eq) in50 mL of DMF was stirred at 65° C. for 7 hours and cooled to roomtemperature. After a filtration, the filtrate was evaporated to an oil,which was chromatographed (DCM/MeOH 20:1) to give a yellow solid, 2.9 g,in 66% yield.

Step 2: Synthesis of 27

A mixture of 7 (1.42 g, 3.938 mmol, 1.0 eq), 2-methoxy-5-nitroaniline(927 mg, 5.513 mmol, 1.4 eq), and 2.5 M HCl/EtOH (6 mL) in 35 mL of2-methoxyethanol was sealed and stirred at 110° C. for 5 hrs and cooledto room temperature. The mixture was worked up with sat. Na2CO3/DCM andpurified with isco (MeOH/DCM 1:20) to give a yellow foam on oil pump,520 mg, in 27% yield.

Step 3: Synthesis of 28

A mixture of the 27 (250 mg, 0.5 mmol), Zn (150 mg) and NH₄Cl (150 mg)in 2 mL of THF/H20 (5:1) was stirred at room temperature for 1.5 hoursand filtered. The filtrate was worked up with saturated Na₂CO₃ and DCM.The crude product was purified with preparation plates to afford ayellow solid, 143 mg, in 61% yield.

Step 4: Synthesis of 29

The aniline (280 mg, 0.606 mmol) was dissolved in 8 mL of DCM and 0.3 mLof triethylamine was added. The mixture was cooled to −35° C. andacryloyl chloride (54.8 mg, 49 μl, 0.606 mmol, 1.0 eq) was added inportions. The reaction was stirred around −30° C. for 15 min andquenched with saturated Na₂CO₃. The mixture was worked up with sat.Na₂CO₃/DCM and purified with preparation plates to give a light brownsolid, 205 mg, in 66% yield.

Procedure: 35 mg (0.0678 mmol) of 29 was dissolved in 1.5 mL of EtOH andPd/C (10%, wet, 5 mg) was added. The mixture was stirred under H₂balloon at room temperature overnight. The mixture was filtered andpurified with a preparation plate to afford a white solid 30, 8.9 mg, in30% yield.

Step 1: Compound 31 was prepared according to the procedure describedfor the synthesis of compound 1 in Example 1, using2-iodo-3-methylaniline instead of 2-iodoaniline as the startingmaterial. A suspension of 31 (0.53 mmol), 2,4,5-trichloropyrimidine (1.0eq), potassium carbonate (1.2 eq), and tetrabutylammoniumhydrogensulfate (0.1 eq) in DMF was stirred at 65° C. for 18 hrs. Uponcooling the reaction mixture was filtered and the filtrate wasconcentrated. The residue was taken up into a mixture of EtOAc andwater. After extraction with EtOAc (3×), the combined organic phaseswere concentrated to give essentially pure material which was useddirectly in next step reaction.

Step 2: A solution of 32 (0.82 mmol), 2-methoxy-5-nitroaniline 33 (1 eq)and TFA (3 eq) in 2-BuOH (3 mL) was heated at 100° C. for 18 hrs. Uponcooling EtOAc and aq. NaHCO₃ were added to the reaction mixture.Extraction (3×) and concentration of combined extracts gave a solidwhich was purified on silica gel column (ISCO machine) with 10% MeOH inCH₂Cl₂ as the eluents, furnishing 34 as a brownish solid (55%).

Step 3: To a suspension of 34 (0.46 mmol) and zinc powder (6 eq) inacetone (9 mL) and water (1 mL) was added ammonium chloride (10 eq) at0° C. After the mixture was stirred at room temperature for 30 min, HPLCindicated a complete conversion. Acetone was removed on rotavap and theresidue was suspended in DCM and water. Filtration was carried out andthe filtrate was extracted with DCM. Concentration of combined organiclayers gave crude aniline 35, which was used in the next step withoutpurification.

Step 4: To a solution of aniline 35 (0.43 mmol) and N,N-diisopropylethylamine (1.1 eq) in DCM (2 mL) was added acryloylchloride (1.05 eq) at 0° C. After the mixture was stirred at roomtemperature overnight, the volatile components were removed on rotavap.The residue was purified on silica gel column with 3% MeOH in DCM aseluents, furnishing amide 36 as beige solid (48 mg, 21%).

A solution of 12 (125 mg, 0.3 mmol), methyl 2-(bromomethyl)acrylate (1.3eq) and N, N-diisopropylethylamine (1.3 eq) in MeCN (5 mL) was heated at80° C. for 2 hrs. LC-MS indicated both mono- and bis-alkylation productswere formed in almost equal amount, with small percentage oftris-alkylation products. The mixture was subjected to a prep-HPLC(reverse phase) purification and then a pre-TLC purification (normalphase silica gel, 10% MeOH in DCM as eluents), furnishing the titlecompound as a tan solid (15 mg, 10%).

2-(Dimethylaminomethyl)acrylic acid 39 was prepared according to aliterature procedure (Synth. Comm. 1995, 25, 641). To a solution of 39(65 mg, 0.5 mmol), coupling reagent TBTU (1.2 eq) and N,N-diisopropylethylamine (3.0 eq) in DMF (5 mL) and DCM (20 mL) was added5 (1 eq). After the mixture was stirred at room temperature overnight,the volatile components were removed on rotavap and the residue waspurified by reverse phase prep-HPLC, furnishing the title compound as atan solid (23 mg, 9%).

Step 1: the starting material 41 was prepared from3-fluoro-4-chlorophenol via nitration and subsequent O-methylation,according to a published procedure (US Patent Publication No.20080300242). The suspension of 41 (1.0 g, 4.86 mmol), 1-methylpiperzine(1 eq) and K₂CO₃ (1 eq) in DMF (20 mL) was heated at 80° C. for 4 hrs.DMF was removed and the residue was partitioned between DCM and water.Extraction and concentration followed by silica gel column chromatograph(10% MeOH in DCM as eluents) furnished 42 (1.26 g, 91%).

Steps 2 and 3: A degassed suspension of 42 (0.96 g, 3.4 mmol),benzophenone imine (1.5 eq), palladium acetate (0.1 eq), xantphos (0.2eq) and cesium carbonate (1.6 eq) in DMF (20 mL) was heated at 110° C.overnight. Upon cooling the reaction mixture was filtered and thefiltrate was concentrated. The solid residue was dissolved in dioxaneand 2M aq. HCl (1:1, 40 mL) and then heated at 70° C. for 2 hrs. Uponremoving dioxane on rotavap, the water layer was washed with DCM andthen basified with aq. NaHCO₃. Extraction and concentration followed bysilica gel column chromatograph (10% MeOH in DCM as eluents) furnished43 (0.41 g, 45%).

Step 4: To a solution of 43 (0.38 g, 1.42 mmol) in THF (15 mL) was addedNaH (2 eq.) under N₂ at 0° C. in multiple portions. After bubbles of H₂were no longer observed, Boc₂O (4 eq.) was added. The resulting reactionmixture was heated at 50° C. and then refluxed for 2 hrs. The reactionwas quenched with MeOH. Usual workup followed by silica gel columnchromatograph (5% MeOH in DCM as eluents) furnished 44 (0.46 g, 88%).

Step 5: With EtOAc as the solvent 44 (0.46 g) was hydrogenated under 50psi to afford 45 (0.42 g, 99%). Upon removing the solvent, the crudematerial was used directly in the next step.

Step 6: A degassed suspension of 45 (0.42 g, 3.4 mmol), 2 (1.5 eq),palladium acetate (0.1 eq), xantphos (0.2 eq) and cesium carbonate (1.3eq) in DMF (10 mL) was heated at 110° C. for 48 hrs. Usual workupfollowed by silica gel column chromatograph (5% MeOH in DCM as eluents)furnished 46 (0.49 g, 64%).

Step 7: To a solution of 46 in DCM was added excessive TFA. After themixture was stirred at room temperature for 2 hrs, the volatilecomponents were removed on rotavap. The residue was dissolved in EtOACand the solution was basified with aq. NaHCO₃. Extraction andconcentration gave 47 as tan solid.

Step 8: Crude 47 (100 mg) was converted to 48 by using the proceduredescribed in Example 14, step 4. The final product was purified byreverse phase prep-HPLC (10.4 mg, 9%).

Step 1: Under N₂, to a suspension of 41 (0.5 g, 2.43 mmol) and NaH (1.5eq) in THF (10 mL) was added dropwise a solution of2-(dimethylamino)ethanol (1.1 eq) in THF (2 mL) at 0° C. The resultingmixture was stirred at room temperature for 3 hrs. Usual workup followedby silica gel column chromatograph (10% MeOH in DCM as eluents)furnished 49 (0.53 g, 79%).

Step 2: To a degassed suspension of 49 (0.275 g, 1.0 mmol), Pd₂(dba)₃(0.1 eq), 2-(di-t-butylphosphino)-N, N-dimethylbiphenylamine (0.1 eq)and sodium t-butoxide (1.4 eq) in dioxane (10 mL) was added a solutionof NH₃ in dioxane (0.5 M in a N₂-sealed bottle, 10 mL). The resultingmixture was heated at 80° C. for 3 hrs. Usual workup followed by silicagel column chromatograph (15% MeOH in DCM as eluents) furnished 50 (0.15g, 55%).

Steps 3 to 7: The poly-substituted aniline 50 was converted to the titlecompound 51 according to the procedure described in Example 18 bysubstituting 50 for 43.

2,4-Dimethoxy-5-nitroaniline 53 was prepared from1,5-difluoro-2,4-dinitrobenzene via double S_(N)Ar substitution togenerate 52 and subsequent mono-reduction of nitro groups, according toa published procedure (J. Org. Chem. 2005, 70, 10660). This wasconverted to the title compound 54 as for Example 14 by substituting 53for 33 and 2 for 32.

Step 1: A degassed suspension of 2-nitro-4-bromoanisole (2.32 g, 10mmol), N,N-dimethyl-1,3-propanediamine (1.1 eq), Pd₂(dba)₃ (0.02 eq),dppf (0.04 eq) and sodium t-butoxide (1.5 eq) in dioxane (20 mL) washeated at 110° C. overnight. Upon cooling the reaction was quenched withwater. The volatile components were removed on rotavap and the residuewas partitioned between EtOAc and water. Extraction and concentrationfollowed by silica gel column chromatograph (15% MeOH in DCM as eluents)furnished 55 (0.66 g, 26%).

Steps 2 to 6: The secondary amine 55 was converted to the title compound56 as for Example 18 by substituting 55 for 43.

Step 1: Acetic anhydride (7.8 mL, 82.6 mmol) was added dropwise withvigorously stirring to a suspension of 3-fluoro-4-aminophenol (10 g,78.6 mmol) in water (20 mL). Insoluble amide started to precipitate as awhite solid in a few minutes. After the reaction mixture was stirred for10 more minutes, the white solid was collected via filtration and washedwith cold water. Silica gel column chromatograph (5% MeOH in DCM aseluent) gave pure 57 (8.75 g, 66%).

Step 2: To a suspension of 57 (8.75 g, 51.73 mmol) and K₂CO₃ (1.1 eq) inTHF (30 mL) was added methyl iodide (1.2 eq). The mixture was heated ina sealed tube at 60° C. overnight. Filtration and concentration followedby silica gel column chromatograph (5% MeOH in DCM as eluent) furnishedpure 58 (7.17 g, 89%).

Step 3: Nitric acid (70%, 3.83 mL) was added dropwise to a solution of58 (7 g) in DCM (70 mL) with vigorously stirring. After stirred at roomtemperature for 1 hr, the reaction mixture was refluxed for 3 hrs. DCMwas removed on rotavap and the residue was washed with cold water andthen subjected to a silica gel column chromatograph purification (5%MeOH in DCM as eluent) to afford 59 (3.26 g, 37%).

Step 4: Poly-substituted nitrobenzene 59 was reduced to correspondinganiline 60 according to the procedure described in Example 14, step 3.

Step 5: Poly-substituted aniline 60 (200 mg, 1 mmol) was coupled withprecursor 2 (1.5 eq) to afford 61 (320 mg, 67%) via the proceduredescribed in Example 18, step 6.

Step 6: N-arylacetamide 61 (320 mg) was heated at reflux in 6N HCl for30 min. After basification, extraction and concentration aryl amine 62was obtained (290 mg, 98%).

Step 7: Crude 62 (150 mg) was converted to 63 by using the proceduredescribed in Example 14, step 4. The final product was purified byreverse phase prep-HPLC (41 mg, 24%).

Step 1: 2,4-Dchloro-7H-pyrrolo[2,3-d]pyrimidine (5.0 g, 27 mmol) wassuspended in MeCN (300 mL) and AcOH (60 mL); to this was addedselectfluor (1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octanebis(tetrafluoroborate), 1.4 eq, 13.2 g) in one portion. The reactionmixture was stirred at 60° C. overnight. HPLC monitoring indicatedcomplete conversion. After the solvents were evaporated to the volume of˜100 mL, toluene (20 mL) was added and the suspension was filtered. Thefiltrate was evaporated to dryness and re-evaporated with toluene (2×20mL). The residue was then purified via a short silica pad (washing with1/1 DCM/EtOAc) and column chromatography (ISCO machine, EtOAc/DCM, EtOAcon a 0-100% gradient) to give the crude product. Upon standing the pureproduct was seen to precipitate from the column fractions. These werefiltered and the mother liquors were combined to precipitate a 2^(nd)crop. Total 1.23 g of the product 64 was obtained (22% yield, ˜90% pure,Cl-isomer was the main impurity).

Step 2: A solution of 64 (1.22 g, 6 mmol) in THF (10 mL) was slowlyadded to a suspension of NaH (1 eq) in THF (10 mL) at 0° C. After themixture was stirred for 10 min, a solution of tosyl chloride (1 eq) inTHF (5 mL) was slowly added. Stirring was continued for 30 min at 0° C.and then at room temperature overnight. The reaction was shown to becomplete via HPLC monitoring and was quenched via the addition of aq.NH₄Cl (1-2 mL). The reaction mixture was then filtered through celiteand the filtrate was evaporated. The crude product was purified viacolumn chromatography (ISCO machine, EtOAc/Heptane, EtOAc on a 0-100%gradient) to give 65 (1.22 g, 56%).

Step 3: In a microwave vessel (20 mL) were placed 65 (600 mg, 1.7 mmol),1 (282 mg, 1.7 mmol) and isopropanol (10 mL). After HCl (1.3 mL, 4 M indioxane) was added, the resulting mixture was stirred in the microwavereactor at 150° C. for 2 hrs. The solvents were evaporated and theresidue was purified via silica column chromatography (ISCO machine,EtOAc/Heptane, 0-100% EtOAc to elute impurities and then MeOH/DCM, 0-20%MeOH) to give pure 66 (900 mg, 54%).

Step 4: Intermediate 66 (493 mg, 1 mmol), 2-methoxy-5-nitroaniline 33(168 mg, 1 mmol), K₂CO₃ (1.4 mmol), Pd₂dba₃ (5 mol %) and X-Phos (10 mol%) were weighed into a 100 mL round bottom flask and placed under N₂.The solvents toluene (10 mL) and tert-butanol (2 mL) were added as amixture and the stirring solution was evacuated and backfilled with N₂three times. The resulting mixture was then stirred overnight at 110° C.HPLC showed the reaction to be complete and the solvents wereevaporated. The residue was purified by silica column chromatography onISCO machine (5% MeOH in DCM as eluents) to give coupling product 67(570 mg, 91%).

Step 5: Poly-substituted nitrobenzene 67 was reduced to correspondinganiline 68 according to the procedure described in Example 14, step 3.

Step 6: Crude aniline 68 (123 mg) was converted to 69 by using theprocedure described in Example 14, step 4. The product was purified bysilica column chromatography on ISCO machine (5% MeOH in DCM aseluents). Yield: 69 mg, 51%.

Step 7: A solution of 69 (60 mg) and TBAF (1 M in THF, 0.3 mL) in THF(10 mL) was refluxed for 5 hrs. HPLC indicated a complete reaction.After the solvent was evaporated, the residue was purified by silicacolumn chromatography on ISCO machine (5% MeOH in DCM as eluents). Theproduct was co-eluted with TBAF; water wash furnished pure product (10mg, 21%).

Step 1: To a suspension of 5-fluoro-2-nitroanisole (50 mmol, 8.5 g) andzinc powder (3.5 eq, 11.4 g) in acetone (45 mL) and water (5 mL) wasadded ammonium chloride (11 eq, 29.3 g) at 0° C. in multiple portions.After the mixture was stirred at r.t. overnight, HPLC indicated acomplete conversion. Acetone was removed on rotavap and the residue wassuspended in DCM and water. Filtration was carried out and the filtratewas extracted with DCM. Concentration of combined organic layers gavecrude aniline (˜7.0 g), which was used in the next step withoutpurification.

Step 2: To a suspension of 4-fluoro-2-methoxyaniline (5.1 g, 36.1 mmol)in concentrated sulfuric acid (55 mL) was added guanidine nitrate (4.38g, 36.1 mmol) in portion wise under ice cooling over 15 min. The mixturewas stirred at the same temperature for additional 15 min. The reactionwas then poured into a saturated cold NaHCO₃ solution and theprecipitated solid were collected by filtration. The residue was takenup in EtOAc and dried over anhydrous Na₂SO₄. The solvent was strippedoff to afford the B (4.72 g).

Step 3: The above compound B (0.1 g, 0.53 mmol) and 4-(ortho dimethylphosphinyl anilino)-5-chloro-2-chloro pyrimidine (0.17 g, 0.53 mmol)were dissolved in a mixture of 2-butanol (1.2 mL) & trifluoroacetic acid(0.25 mL) and were heated to 100° C. in a seal tube for overnight. Thereaction mixture was then cooled to rt and poured into a saturatedNaHCO₃ solution while stirring to afford an orange solid which wasfiltered, washed with Et₂O to remove final traces of water. The productwas dried to afford C (0.19 g) which was directly used in the next step.

Step 4: NaH (0.039 g, 0.96 mmol, 60% dispersion in oil) was taken up ina dry capped microwave vial. To this,1-(2-hydroxyethyl)-4-methylpiperazine (0.023 g, 0.16 mmol) dissolved indry tetrahydrofuran (1.6 mL) was added dropwise. The mixture was stirredat rt for 20 min. Intermediate C (0.075 g, 0.16 mmol) was then added inone portion to this suspension and the mixture was heated to 67° C. inthe closed seal tube for 25 min. The mixture was allowed to reach at rtand quenched with a few drops of methanol. Solvent was removed undervacuum and the resultant crude was subjected to FCC eluting withDCM-MeOH (95/5) to furnish the desired product D (0.081 g).

Step 5Compound D (0.078 g, 0.13 mmol) was dissolved in a mixture ofacetone (1.3 mL) and water (0.3 mL). To this, zinc nano powder (0.07 g,1.3 mmol) was added immediately followed by addition of NH₄Cl (0.16 g,2.6 mmol) in small portions. The mixture was vigorously stirred at r.tfor 30 min. Anhydrous Na2SO4 was then added to this stirring mixture andthe resultant crude was filtered, solvents were evaporated and theresidue were taken up in DCM and directly loaded on the silica gelcartridge and eluted with DCM-MeOH—NH₃ (90/10) to furnish the desiredproduct E (0.044 g).

Step 6: To a solution of E (0.044 g, 0.078 mmol) in dry tetrahydrofuran(0.52 mL) was added DIPEA (0.027 mL, 0.156 mmol) at 0° C. understirring. This was followed by the addition of acryloyl chloride (0.007g, 0.078 mmol). The reaction was stirred at that temperature foradditional 1 h. Solvent was stripped off under vacuum and the crude waspurified by FCC using DCM-MeOH—NH₃ (90/10) to furnish a gum which wasfurther triturated with Et₂O to furnish a solid material F (0.02 g).

Step 1: The suspension of advanced intermediate C,(3-dimethylamino)pyrrolidine (1 eq) and K2CO3 (2 eq) in DMF was stirredat r.t. overnight. The solid components were filtered off and thefiltrate was concentrated on rotavap and then on vacuum pump. Theresidue was essentially pure by HPLC analysis and was used directly inthe next step.

Steps 2 and 3: these were carried out according to the procedureoutlined in Scheme 24, steps 5 and 6.

The suspension of N-Boc-pyrrolidin-3-one, secondary amines, sodiumcyanoborohydride and magnesium sulfate in DCM was stirred at 40° C.overnight. After the solid components were removed by filtration, 2.5NHCl in MeOH was added to the filtrate and the resulting solution wasstirred at r.t. for 30 min. Volatile components were removed on rotavap;the residue was partitioned between DCM and aq. NaHCO3. Combined organicphases were concentrated and the residue was purified by silica gelcolumn chromatography to furnish (3-dialkylamino)pyrrolidine C, whichwas converted into final compounds by substituting C for(3-dimethylamino)pyrrolidine.

Secondary amines were converted into 2-(dialkylaminomethyl)acrylic acidA according to a literature method (Synth. Comm. 1995, 25, 641). Thesewere converted into final compounds according to the procedure outlinedin Scheme 17 by substituting A with 39.

2-Fluoro-5-nitroaniline or 2-methyl-5-nitroaniline was converted intodesired compound according to the procedure outlined in Scheme 28.

Step 1: the starting material A underwent a S_(N)Ar reaction withintermediate 2 according to the procedure described in step 1 of Example14.

Step 2: To a solution of compound B (246 mg, 0.5 mmol), coupling reagentTBTU (1.2 eq) and N, N-diisopropylethylamine (3.0 eq) in DMSO (10 mL)was added piperazine (1 eq). After the mixture was stirred at roomtemperature overnight, water and DCM was added to facilitate extraction.Combined extracts were washed with water to remove DMSO. After dryingover Na2SO4 and concentration on rotavap the residue was purified bysilica gel column chromatography with 5% MEOH in DCM as the eluents,furnishing compound C as a tan solid (154 mg, 54%).

Step 3: A solution of compound C (570 mg) and BH3-Me2S (2.0 M in THF, 5eq, 0.6 mL) in THF (5 mL) was stirred at r.t. overnight. 6N aq. HCl (15mL) was added and the resulting solution was stirred at r.t. for 5 hr.Solid K2CO3 was carefully added to basify the reaction mixture. Afterextractions with DCM the combined organic phases were dried,concentrated and purified by silica gel column chromatography with 5%MeOH in DCM as the eluents, furnishing compound D as a tan solid (300mg, 54%).

Steps 4 and 5: Compounds C and D were converted into final compounds Eand F respectively according to the procedure described in Example 14.

Compound A was synthesized according to the procedure outlined in Scheme25 by substituting 3-(tert-butoxycarbonylamino)pyrrolidine for3-(dimethylamino)pyrrolidine. Standard de-protection of Boc with TFA-DCMfollowed by basification and silica gel column chromatography (5% MeOHin DCM as the eluents) furnished title compound.

Step-1: Synthesis of 61:

To a mixture of compound 2 (420 mg) in THF (2.0 mL) was added maleicanhydride (1.0 eq) at room temperature. The reaction was stirred at roomtemperature for 1 hour. The product was obtained by filtration and thenwashed with DCM (2.0 mL) to yield the product, 61, as a yellow solid(435 mg, yield 84%).

Step-2: Synthesis of Examples 62, 63 and 64

General procedures: The compound of Example 61 (77 mg, 0.15 mmol),prepared as in Step-1 (immediately above), was dissolved with therespective amine (0.15 mmol, 1.0 eq.) in dry DMF (2.0 mL). HBTU (80 mg)was added and followed by Et₃N (30 uL). The contents were stirred atroom temp for 1 h. Solvent was removed in vacuo and the residue waspurified by a prep-TLC plate (6.5% MeOH/DCM). The corresponding bandswere collected to give the final products:

Synthesis of Example 75

A solution of compound 2 (84 mg) in DCM (3.0 mL) and Et₃N (0.1 mL) wastreated with Ethyl fumaroyl chloride (1.05 eq). The contents werestirred at room temp for an hour. Solvent was removed in vacuo and theresidue was purified by a prep-TLC plate (7.5% MeOH/DCM) to give theproduct as a yellow solid (34 mg, yield 31%).

Step-1

Example 75 (360 mg) in MeOH (1.5 mL) and water (0.5 mL) was treated withK₂CO₃ (1.0 g) at 50° C. for 2 h. The reaction mixture was cooled down toroom temperature. The organic solution was transferred to a new vial anddiluted with DCM (3.0 mL). The pH was adjusted to 6-7 by addinghydrochloric acid. The resulting organic layer was evaporated and theresidue was washed with MeOH to give product as a yellow solid (304 mg,yield 89%)

Step-2

Compounds for Examples 60, 59 and 58 were made according to the generalprocedure for Example 62, using the appropriate amine:

Step-1

A mixture of 1,1-dimethylpropargylamine (4.2 g) and Boc₂O (11 g) withoutsolvent was warmed up to 50° C. for 30 min. The resulting solid wastreated with n-hexane (10 mL) and the product was collected byfiltration to give white solid (7.6 g, yield 82%)

Step-2

To a mixture of compound A (527 mg) and step-1 product (250 mg) in DMF(5.0 mL), was added (Ph₃P)₂PdCl₂ (0.1 g), CuI (0.05 g) and Et₃N (0.2mL). The mixture was stirred at 80° C. for 4 h. The reaction mixture wasconcentrated and the residue was purified by a prep-TLC plate (8%MeOH/DCM) to give final product as a yellow solid (430 mg, yield 68%).

Step-3

Water was added dropwise to a mixture containing the product of step-2(240 mg) in acetone (1.0 mL), Zn dust (0.3 g) and NH₄Cl (0.15 g). Themixture was stirring at room temperature for 15 min and then dilutedwith DCM (5 mL). After filtration, the organic solution was evaporatedand the residue was used for next step.

Step-4

The residue from Step-3 was dissolved in THF (3.0 mL) and Et₃N (0.05mL), and the resulting solution was treated with acroyl chloride. Thereaction was monitored by HPLC until disappearance of starting material.The reaction was then quenched with aq.NaHCO₃ and extracted with DCM(2×5.0 mL). The organic solution was concentrated and the residue waspurified by a prep-TLC plate (10% MeOH/DCM) to give product as a yellowsolid (112 mg, yield 45% for two steps).

Step-5

A solution of the product of Step-4 (80 mg) in MeOH (1.0 mL) and DCM(0.5 mL) was treated with TFA (0.5 mL) at 0° C. The mixture warmed up toroom temperature for 1 h. Solvent was evaporated, the residue wasneutralized with aq. NaHCO3, and the neutralized material was subjectedto prep-TLC plate (20% MeOH/DCM) to give the desired product, 65, as alight yellow solid (42 mg, yield 62%).

Step-1

To a mixture of 2,2-dimethyl-1,3-dioxan-5-one (2.6 g), dimethyl amineHCl salt (1.8 g) in DCM (50 mL) was added NaHB(OAc)₃ (6.0 g) and Et₃N(3.0 mL). The reaction mixture was stirred at room temperature overnightand then diluted with aq.NaHCO3. The organic layer was dried andevaporated to give colorless oil (2.5 g, yield 79%).

Step-2

A solution of step-1 product (2.4 g) in MeOH (5.0 mL) was treated withHCl (10 mL, 2N). The mixture was heated to reflux for 15 min. Solventwas evaporated and the residue was dissolved in DCM (6.0 mL). Theorganic solution was dried, filtered and evaporated to give colorlessoil (1.5 g, yield 77%).

Step-3

The nitro compound was synthesized by reacting compound B and theproduct of step-2 according the general procedure.

Step-4

Reduction of the nitro group and formation of the correspondingacrylamide was carried out according to the procedure in Scheme 32,step-3 and step-4.

Step 1: To a solution of benzyl glycidyl ether (5.0 g) in MeOH (5.0 mL)was added NaOMe (5.0 mL, 25% in methanol). The mixture was warmed up to50° C. for 1 h and then heated to reflux for 5 min. The mixture wastreated with wet NaHCO₃ and filtered. Solvent was evaporated and theresidue was dissolved in DCM (20 mL). The solution was dried andevaporated to give yellowish oil (4.8 g, yield 80%).

Step 2: A solution of step 1 product (3.0 g) in DCM (100 mL) was treatedwith PDC (6.0 g) and molecular sieves (4.0 g). The mixture was stirredat room temperature for 4 h and diluted with Et₂O (100 mL). The mixturewas filtered through a Celite pad and solvent evaporated to give yellowoil (1.7 g, yield 57%).

Step 3: The compound was synthesized according to the followingprocedure: To a mixture of 2,2-dimethyl-1,3-dioxan-5-one (2.6 g),dimethyl amine HCl salt (1.8 g) in DCM (50 mL) was added NaHB(OAc)₃ (6.0g) and Et₃N (3.0 mL). The reaction mixture was stirred at roomtemperature overnight and then diluted with aq.NaHCO3. The organic layerwas dried and evaporated to give colorless oil (2.5 g, yield 79%).

Step 4: A solution of step-3 product (1.5 g) in MeOH (10 mL) was chargedwith Pd—C (0.5 g, 10% wet) and hydrogenated under a hydrogen balloon atroom temperature overnight. The catalyst was filtered off and thesolvent was evaporated to give the product (0.64 g, yield 71%) ascolorless oil.

Step 5: The compound was synthesized according the general procedurefrom compound B and step-4 product as a yellow solid.

Step 6: Example 37 was synthesized according to a similar procedure tothe following: To a mixture of tert-butyl(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-nitrophenyl)-2-methylbut-3-yn-2-yl)carbamate(240 mg) in acetone (1.0 mL) and Zn dust (0.3 g), NH₄Cl (0.15 g), wasadded drops of water. The mixture was stirring at room temperature for15 min and then diluted with DCM (5 mL). After filtration, the organicsolution was evaporated and the residue was used for next step. Theresidue was dissolved in THF (3.0 mL) and Et₃N (0.05 mL) and solutionwas treated with acroyl chloride. The reaction was monitored by HPLCuntil start material disappear. The reaction was quenched with aq.NaHCO₃and extracted with DCM (2×5.0 mL). The organic solution was concentratedand the residue was purified by a prep-TLC plate (10% MeOH/DCM) to givethe desired product.

Step 1: To a solution of N,N′-dimethylethylenediamine (300 mg) in DMF(2.0 mL) was added K₂CO₃ (1.0 g) and compound B (466 mg). The mixturewas heated at 80° C. for 3 h. Solvent was evaporated and the residue wasextracted with DCM and then purified by a prep-TLC plate (10% MeOH/DCMwith 1% NH₃ in methanol) to give product as a yellow solid (400 mg,yield 75%).

Step 2: A solution of step 1 product (1 eq) in DMF (3.0 mL) was treatedwith NaHCO₃ (0.5 g) and the respective bromide (2.5 eq) at 50° C. for 5h. Solvent was evaporated and the products were purified by a prep-TLCplate (8% MeOH/DCM) to give product as yellow solids.

Step 3: Reduction of the nitro group and formation of the correspondingacrylamide was carried out according to the procedure in Scheme 32,step-3 and step-4.

The methoxy- and fluoro-ompounds below were synthesized by this method:

and were converted to the corresponding acrylamides. See Example 67.

Step 1: A mixture of N-(2-methoxyethyl)methylamine (1.8 g) and ethylbromoacetate (3.4 g) in acetonitrile (20 mL) was treated with K₂CO₃ (4.0g) and NaI (20 mmol). The mixture was refluxed overnight. Solvent wasevaporated and the residue was extracted with DCM and then purified onSilica gel column (0-8% MeOH/DCM) to give the product as colorless oil(3.2 g, yield 93%).

Step 2: To a solution of step-1 product (3.5 g) in THF (20 mL) was addedLAH (800 mg) portion wise. The resulting mixture was stirred at roomtemperature overnight and then quenched with EtOAc and water. Afterfiltration, the organic solution was evaporated to give colorless oil(2.0 g, yield 75%).

Step 3: The step 3 product compound was synthesized according thegeneral procedure from compound B (400 mg) and step-4 product to givethe title compound as a yellow solid (200 mg, yield 40%).

Step 4: Example 39 was synthesized according to a similar procedure tothat used in Step 6 of Example 37.

Step-1

To a mixture of 1-Boc-3-pyrrolidine (1.85 g), azetidine (0.65 g) in DCM(10 mL) was added NaHB(OAc)₃ (3.5 g) and molecular sieves (3.0 g). Thereaction mixture was stirred at room temperature for 3 h and dilutedwith aq.NaHCO₃. The organic layer was dried and evaporated. The residuewas column purified on Silica gel (5% MeOH/DCM) to give the product as awhite solid (1.6 g, yield 71%).

Step-2

To a solution of step-1 product (230 mg) in MeOH (1.0 mL) was added HClin dioane (3.0 mL, 4.0M solution) at room temperature. The mixture wasstirred for 1 h and solvent evaporated to give white solid for nextstep.

Step-3

To a mixture of compound B (450 mg), product of step-2 in DMF (3.0 mL)was added molecular sieves (1.0 g) and K₂CO₃ (1.0 g). The reactionmixture was heated at 60° C. for 30 min. Solvent was evaporated and theresidue was purified by a prep-TLC plate (10% MeOH/DCM) to give productas a yellow solid (380 mg, yield 69%).

Step-4

Step-4 was carried out using the procedures of Scheme 32 step-3 andstep-4 to yield the desired product (Example 68) as a yellow solid (44mg)

B.

Step-1

To a mixture of compound B (3.0 g) and 4-piperidinone HCl salt in DMF(5.0 mL) was added K₂CO₃ (2.5 g). The mixture was heated at 70° C. for 3h and solvent was evaporated.

The residue was extracted with DCM and purified by CombiFlash(MeOH/DCM).The product (1.6 g, yield 46%) was obtained as a red solid.

Step-2

General procedure of reductive amination: To a mixture of step-1 product(275 mg), respective amines (1.5 eq) in DCM was added NaHB(OAc)₃ (2 eq)and molecular sieves (0.3 g). The resulting mixture was shaked at roomtemperature for 4 h and treated with wet NaHCO₃. The organic solutionwas separated and purified by prep-TLC plates (7-15% MeOH/DCM) to giveproducts.

Compounds synthesized by this method:

Step-3

Reduction of the nitro group and formation of the correspondingacrylamide was carried out according to the procedure in Scheme 32,step-3 and step-4.

Step-1

To a solution of cyclopropyl(trimethylsilyl)acetylene (13.8 g) in ether(200 mL) was added n-BuLi (40 mL, 2.5M in hexane). The reaction mixturewas stirred at room temperature overnight. The dark-yellow solution wascooled to −78° C. and a large excess of powdered dry ice was added inportions. The reaction mixture was allowed to warmed up to roomtemperature and poured into ice-cooled water. The layer was separated,and the aqueous layer was washed with Et₂O, acidified by adding 12Naq.HCl solution and extracted with Et₂O. The organic layer was dried andconcentrated to give the title compound as a white solid (8.5 g, yield47%).

Step-2

To a solution of step-1 product (1.8 g) and DPPA (2.79 g) in t-BuOH (30mL) was added Et₃N (2.02 g). The mixture was refluxed for 20 h. Solventwas evaporated and the residue was column purified on Silica gel (20%Et₂O)/heptane) to give the product as a white solid (1.3 g, yield 52%).

Step-3

A solution of step-2 product (1.2 g) in THF (10 mL) was treated withn-Bu₄NF (6.0 ml, 1.0M solution in THF). The mixture was stirred at roomtemperature for 1.5 h and solvent was evaporated. The residue was columnpurified on Silica gel (20% Et₂O)/heptane) to give the product as awhite solid (0.75 g, yield 87%).

Step-4

The product of Step-3 was then reacted with Compound A using theprocedure of Scheme 32, step-2.

Step-5

To a solution of step-4 product (250 mg) in DCM was added HCl in dioxane(1.5 mL, 4.0M solution) at −78° C. The mixture was warmed up slowly toroom temperature. Solvent was evaporated and the residue was treatedwith aq.K₂CO₃ and then purified by a prep-TLC plate (10% MeOH/DCM) togive yellow solid (150 mg).

The yellow solid was dissolved in DCM (3.0 mL) and treated with formylaldehyde (5 drops, 40% aq. solution) and MgSO4 (0.5 g, anhydrous) for 30min. To the mixture was added NaBH(OAc)₃ (2 eq). The reaction mixturewas stirred for 1 h and diluted with aq. NaHCO₃. The mixture wasextracted with DCM and product was and purified by prep-TLC plates (10%MeOH/DCM) to give yellow solid (50 mg, yield 23%).

Step-6

Reduction of the nitro group and formation of the correspondingacrylamide was carried out according to the procedure in Scheme 32,step-3 and step-4, to produce the final product pictured above (Example73).

Step 1: To a solution of 3-methoxy-4-nitrobenzyl alcohol (5 g) in DCM(100 mL) was added PDC (1.5 eq) and molecular sieves (6.0 g). Themixture was stirred at room temperature for 2 h and diluted with Et₂O(100 mL). The mixture was filtered through a Celite pad and solvent wasevaporated. The residue was washed with a small amount MeOH to give offwhite solid (3.7 g, yield 74%).

Step 2: To a solution of step-1 product (0.91 g) in DCM (10 mL) wasadded (Ethoxycarbonylmethlene)triphenylphosphorane (2.0 g). The mixturewas stirred at room temperature for 30 min. Solvent was evaporated andthe residue was column purified on Silica gel (20% Et₂O)/heptane) togive a yellowish solid (1.1 g, yield 87%).

Step 3: A solution of step-2 product (0.52 g) in MeOH (10 mL) wascharged with Pd—C (0.5 g, 10% wet) and hydrogenated under a hydrogenballoon at room temperature overnight. The catalyst was filtered off andsolvent was evaporated to give yellow oil (0.45 g, yield 97%).

Step 4: A vial was charged with H₂SO₄ (2.0 mL) and cooled to 0° C.Step-3 product (0.4 g) was carefully introduced. Guanidine nitrate (1eq) was added. The mixture was stirred at 0° C. for 2 h and at roomtemperature for 1 h. The mixture was treated with excess wet NaHCO3 andextracted with DCM (10 mL). The product was and purified by prep-TLCplates (8% MeOH/DCM) to give orange solid (0.34 g, yield 71%).

Step 5: A solution of compound C (320 mg), step-4 product (268 mg) andTFA (0.3 mL) in 2-BuOH (2 mL) was heated at 100° C. for 18 hrs. Uponcooling EtOAc and aq. NaHCO₃ were added to the reaction mixture.Extraction (3x) and concentration of combined extracts gave a solidwhich purified by prep-TLC plates (15% MeOH/DCM) to give orange solid(410 mg, yield 71%).

Step 6: To a suspension of step-5 product (400 mg) in MeOH (2.0 mL) wasadded K₂CO₃ (1.0 g) and water (0.5 mL). The reaction vial was capped andheated at 60° C. for 15 min. The mixture was cooled down to roomtemperature and the top layer was transferred to a new vial and dilutedwith water. The pH was adjusted to 5-6 by adding aq HCl (2N) and theproduct was collected by filtration as a yellow solid (310 mg, yield86%).

Step 7: To a mixture of step-6 product (260 mg) and Et₂NH (1.1 mmol) inDMF (2.0 mL) was added HBTU (1.3 mmol) and Et₃N (0.14 mL). The mixturewas stirred at room temperature for 2 h and diluted with DCM (5.0 mL).The mixture was washed with aq. K₂CO₃ and evaporated. The residue waspurified by prep-TLC plates (15% MeOH/DCM) to give an orange solid (250mg, yield 87%).

Step 8: To a solution of step-7 product (250 mg) in THF (1.0 mL) wasadded BH₃Me₂S (4.0 mL, 2.0M solution in THF). The mixture was stirred at60° C. for 2 h and solvent was evaporated. The residue was dissolved inMeOH (2.0 ml) and treated with wet K₂CO₃ in a capped vial at 70° C. for1 h. The organic solution was evaporated and the residue was purified byprep-TLC plates (25% MeOH/DCM) to give an orange solid (170 mg, yield70%).

Step 9: Reduction of the nitro group and formation of the correspondingacrylamide was carried out according to the procedure in Scheme 32,step-3 and step-4, to produce the final product.

Step 1: N,N-diethyl-2-(3-methoxy-4-nitrophenyl)acetamide was made inaccordance with the methods disclosed herein.

Step 2: To a solution ofN,N-diethyl-2-(3-methoxy-4-nitrophenyl)acetamide (1.0 g) in THF (5.0 mL)was added BH₃Me₂S (20. mL, 2.0M solution in THF). The mixture wasstirred at 60C for 2 h and solvent was evaporated. The residue wasdissolved in MeOH (10 ml) and treated with wet K₂CO₃ in a capped vial at70° C. for 1 h. The organic solution was evaporated and the residue waspurified on Silica gel column (5% MeOH/DCM) to give the product as anorange oil (0.62 g, yield 65%)

Step 3: A solution of step-2 product (600 mg) in MeOH (10 mL) wascharged with Pd—C (0.5 g) and hydrogenated under a hydrogen balloon atroom temperature for 3 h. The catalyst was filtered off and the solventwas evaporated to give a yellow oil (430 mg, yield 81%)

Step 4: The product of step 4 was synthesized according the procedure ofstep 4 of Scheme 39 as an orange oil.

Step 5: The product of step 4 was synthesized according the procedure ofstep 5 of Scheme 13 to afford an orange solid.

Step 6: Reduction of the nitro group and formation of the correspondingacrylamide was carried out according to the procedure in Scheme 32,step-3 and step-4, to produce the final product.

Step 1: A mixture of glycidyl methyl ether and aq. methylamine (1.5 eq)was heated at 55° C. for 2 hr. Removal of volatile components gaveintermediate A which was used directly in next step.

Step 2: Intermediate A (400 mg, 3.34 mmol, 1.0 eq) in 4 ml of dioxaneand 4 ml of water was adjusted to pH 12 with 4M NaOH, and cooled to 0°C. O(Boc)2 (806 mg, 3.69 mmol, 1.1 eq) was added in 2 portions and themixture was stirred at R.T. overnight. The mixture was evaporated toreduce volume by one half and then treated with sat. NaHCO3 (3 ml). Thiswas extracted with EtOAc (3×25 ml), dried, evaporated, andchromatographed (EtOAc/Heptane 1:2 to 1:1) to give an oil, 703 mg, in96% yield.

Steps 3-5: the chemistry was carried out following the proceduresdescribed in Scheme 24.

Step 6: to a solution of intermediate B (304 mg) in DCM (5 mL) was addedTFA (1.8 mL). The mixture was stirred at rt for 1 h then quenched withsaturated sodium bicarbonate solution until pH=8.0. The organics wereextracted with DCM (3×) and the combined organics were dried overanhydrous sodium sulfate, and the solvents were removed under reducedpressure to give the desired product as a pale brownish solid (262 mg,95%).

Example 128

Step-1: to a solution of compound 71 (527 mg, 1.0 mmol) andtert-butyl(3-butynyl)carbamate (400 mg) in DMF (4.0 mL), was added(Ph₃P)₂PdCl₂ (0.1 g), CuI (0.05 g) and Et₃N (0.2 mL). This degasedmixture was stirred at 80° C. for 3 h. The reaction mixture wasconcentrated and the residue was purified by a prep-TLC plate (8%MeOH/DCM) to give compound 73 as a yellow solid (280 mg, yield 46%).

Step-2: compound 73 (280 mg, 0.46 mmol) was dissolved in DCM (2.0 mL)and treated with HCl in dioxane (1.0 mL, 4.0 M) at room temperature for20 min. Solvent was evaporated and the residue was treated with aq.sodium bicarbonate and extracted with DCM. Combined organic layers weredried and evaporated to give compound 74 (220 mg, 93%) as yellow solid.

Step-3: to a suspension of compound 74 (220 mg, 0.43 mmol) and MgSO₄(0.5 g) in DCM (3.0 mL) was added 4 drops of formaldehyde solution(36.5%). After the resulting mixture was stirring for 20 min NaHB(OAc)₃(250 mg) was added. The mixture was heated at 50° C. for 30 min and thenquenched with aq. NaHCO₃. The product was purified by prep. TLC(DCM:MeOH=100:15) to give compound 75 (180 mg, 78%) as yellow solid.

Step-4: to a suspension of compound 75 (180 mg) and Zn dust (0.3 g) inacetone (1.0 mL) was added NH₄Cl (0.15 g) and drops of water. Themixture was stirring at room temperature for 15 min and then dilutedwith DCM (5 mL). After filtration, the organic solution was evaporatedand the residue (140 mg) was used for next step.

Step-5: to a solution of compound 76 (˜140 mg) in DCM (3.0 mL) was addedacrylic acid (0.076 mL), EDC (200 mg), Et₃N (0.2 mL). The mixture wasstirring at room temperature for 3 h. Solvent was evaporated and theresidue was purified by prep TLC (DCM: MeOH=100:15) to give titlecompound (40 mg, 26%) as light yellow solid.

Example 129

Using the procedure described in step 1 of Scheme 41 R-(−)-glycidylmethyl ether was converted into amino alcohol A. Title compound wasobtained from transformation of A via a 3-step chemical sequence, asdescribed in Scheme 24.

Example 130

Title compound was prepared in a manner similar to Example 129 usingS-(+)-glycidyl methyl ether as starting material.

Example 131

Title compound was prepared in accordance with the method described inScheme 12 by substituting 2,4-dichloro-5-methoxypyrimidine for5-bromo-2,4-dichloropyrimidine.

Example 132

Title compound was prepared in accordance with the method described inScheme 5 by reacting intermediate 5 with 2-chloroacryloyl chloride.

Example 133

Title compound was prepared in accordance with the method described inScheme 12 by substituting 2,4,5-trichloropyrimidine for5-bromo-2,4-dichloropyrimidine and 2-methoxy-4-methyl-5-nitroaniline for2-methoxy-5-nitroaniline.

Example 134

Title compound was prepared in accordance with the method described inScheme 12 by substituting 2,4,5-trichloropyrimidine for5-bromo-2,4-dichloropyrimidine and 2-(trifluoromethoxy)-5-nitroanilinefor 2-methoxy-5-nitroaniline.

Example 135

Title compound was prepared in accordance with the method described inScheme 12 by substituting 2,4,5-trichloropyrimidine for5-bromo-2,4-dichloropyrimidine and 2-ethyl-5-nitroaniline for2-methoxy-5-nitroaniline.

Synthesis of Triazine Compound with CF₃ at R^(a2):

Title compound was prepared in accordance with the method described inScheme 12 by substituting 2,4-dichloro-1,3,5-triazine for5-bromo-2,4-dichloropyrimidine and 2-(trifluoromethoxy)-5-nitroanilinefor 2-methoxy-5-nitroaniline.

Example 136

Title compound was prepared in accordance with the method described inScheme 12 by substituting 2,4,5-trichloropyrimidine for5-bromo-2,4-dichloropyrimidine and 2-chloro-5-nitroaniline for2-methoxy-5-nitroaniline.

Example 137

Title compound was prepared in accordance with the method described inScheme 5 by reacting intermediate 5 with 2-chloroacetyl chloride.

Example 138

To a suspension of NaH (0.67 g, 5 eq) in THF (30 mL) was added dropwisea solution of oxetane-3-ol (0.24 g, 1 eq) in THF (5 mL) under N2 at r.t.After the mixture was stirred at r.t. for 1 hr, 2-fluoro-5-nitroaniline(0.51 g, 1 eq) was added. The resulting mixture was heated at 70° C. for3 hr and then quenched with water. Concentration removed THF and theresidue was taken up in DCM. Extraction, concentration and purificationon silica gel column (0-100% EtOAc in heptane) furnished intermediate Aas a yellow oil (52%).

Intermediate A was converted into desired final compound via a 3-stepsequence outlined in Scheme 28.

Example 139

Zinc cyanide (70 mg, 0.65 eq), intermediate 27 (490 mg, 1 eq), Pd2(dba)3(46 mg, 0.05 eq), DPPF (69 mg, 0.13 eq) was placed in a microwave tubecontaining DMF-H₂O (3 mL). This mixture was flushed with Ar and thenheated at 130° C. for 1.5 hr. The reaction mixture was evaporated andthe residue was purified on silica gel column (0-5% MeOH in DCM)furnished intermediate A as a yellow solid (32%).

Intermediate A was converted into desired final compound via a 2-stepsequence outlined in Scheme 12.

Example 140

Title compound was prepared in a manner similar to Example 133 bysubstituting 2-chloroacetyl chloride for acryloyl chloride in last step.

Example 141

Title compound was prepared in a manner similar to Example 137 bysubstituting 2,4-dichloro-5-methylpyrimidine for2,4,5-trichloropyrimidine.

Example 142

Title compound was prepared in accordance with the method described inScheme 43 by substituting (+)-glycidyl ethyl ether for R-(−)-glycidylmethyl ether.

Examples 143-146

The title compounds were prepared in accordance with the methoddescribed in Scheme 24 by substituting aniline A for2-methoxy-4-fluoroaniline and optically pure1-(dimethylamino)-3-methoxy-2-propanol for1-(2-hydroxyethyl)-4-methylpiperazine.1-(dimethylamino)-3-methoxy-2-propanol was synthesized via a proceduredescribed in Scheme 43.

Example 147

Title compound was prepared in accordance with the method described inScheme 5 by reacting intermediate 5 with 2-fluoroacetyl chloride.

Example 148

Title compound was prepared in accordance with the method described inScheme 28 by substituting 2-chloroacetyl chloride for acryloyl chloridein last step.

Example 149

Title compound was prepared in accordance with the method described inScheme 22 by substituting 2-chloroacetyl chloride for acryloyl chloridein last step.

Example 150

Title compound was prepared in accordance with the method described inScheme 5 by reacting intermediate 5 with (chloromethyl)sulfonylchloride.

Examples 151, 152, and 156

Steps 1-2: the chemistry was carried out according to the proceduredescribed for steps 2 and 3 in Scheme 24.

Step 3: Into a Schlenk flask was loaded intermediate C (260 mg),PdCl2(PPh3)2 (5 mol %) and Cul (10 mol %). This flask was capped with arubber septum and then degassed under vacuum for 1 min before N2 refill.Anhydrous DMF (4 mL) was added followed by the addition of DIPEA (0.1mL) and 1-(dimethylamino)-3-butyne (0.1 mL, note this alkyne was purgedwith dry N2 gas immediately before use). The flask was sealed and themixture was stirred at 80° C. for 16 h. Upon cooling, the reactionmixture was taken up in EtOAc and water. Extraction and concentration ofcombined organic layers afforded crude D which was used directly in thenext step.

Steps 4-5: the chemistry was carried out according to the proceduredescribed for steps 3 and 4 in Scheme 12.

Example 153

Title compound was prepared in accordance with the method described inScheme 48 by substituting 2-(isopropylsulfonyl)aniline for2-(dimethylphosphoryl)aniline.

Examples 154 and 155

Step 1: To a stirred mixture of diethylamine (10.3 ml, 99.6 mmol),3-chloro-3-methylbut-1-yne (10.2 g, 99.6 mmol), triethylamine (16.7 mL,119 mmol), and THF (100 mL) at 0° C. was added copper (I) chloride(0.986 g, 9.96 mmol). The resulting suspension was allowed to warm toroom temperature, and stirring continued for 4 hours. The reactionmixture was partitioned between diethyl ether (250 mL) and a saturatedaqueous solution of NaHCO₃ (100 mL). The phases were separated, and theaqueous phase was re-extracted with diethyl ether (100 mL). The combinedorganic phases were dried (Na₂SO₄), filtered, and concentrated. Thebrown oil was distilled (105-110^(°) C) at atmospheric pressure underN₂. The product A was obtained as an oil (1.85 g, 9%).

Steps 2-4: intermediate A was converted into desired final compound inaccordance with the method described in Scheme 48 by substituting A forN,N-dimethylpropargylamine.

Example 160

Step 1: to a solution of (N-Boc)propargylamine (3.1 g) in DMF (20 mL)was slowly added NaH (1.1 eq) at 0° C. under N2. After the mixture wasstirred at r.t. for 1 hr, methyl iodide (1.1 eq) was added at 0° C. Icebath was removed and the flask was warmed up naturally to r.t. Water wasadded to quench the reaction. After removal of solvents the residue wastaken up in EtOAc and water. Extraction and concentration of combinedorganic phases gave essentially pure A (95%).

Steps 2-4: Intermediate A was converted into compound B in accordancewith the method described in steps 3-5 of Scheme 48 by substituting Afor N,N-dimethylpropargylamine.

Step 5: to a solution of compound B (189 mg) in DCM (3 mL) was added TFA(1 mL). The mixture was stirred at rt for 1 h. The volatile componentswere removed under reduced pressure to give a cloudy residue.Trituration with MTBE followed by filtration and wash with MTBE gave thedesired product as a off-white powder (92 mg, 57%).

Example 164

Title compound was prepared in accordance with the method described inScheme 12 by substituting 2,4,5-trichloropyrimidine for5-bromo-2,4-dichloropyrimidine and3-amino-4-(dimethylphosphoryl)-pyridine A for2-(dimethylphosphoryl)aniline 1. Compound A was prepared in accordancewith the method described in step 1 of Scheme 1 for the synthesis ofintermediate 1 using 3-amino-4-iodopyridine instead of 2-iodoaniline asstarting material.

Examples 157, 158, 159, 161,162, 165, 166, 167, 168, 177, 178, 179,182,183, 184

Step 1: a solution of appropriate secondary amine and propargyl bromide(supplied as a solution in toluene) in ether was stirred at 0° C. thenr.t. for 3 hr. The precipitate was filtered off and the filtrate wascarefully distilled to furnish product A. Contamination of A with smallamount of toluene was unavoidable in some cases but this did not affectnext step reaction. Certain compounds A with relatively high boilingpoints were purified by silica gel column chromatography (5% MeOH inDCM) to remove residual secondary amine which was found to directlydisplace the bromide in the next step.

Steps 2-4: Crude or pure A was converted into desired final compound inaccordance with the method described in Scheme 48 by substituting A forN,N-dimethylpropargylamine.

Example 180, 181

The corresponding propargyl nitro compound was prepared as describedabove, and the E and Z isomers of the reduced amino intermediate wereseparately recovered. Acroylation using the general procedure yieldedthe title compounds:

Example 185

IM1 was prepared according to a literature procedure (WO 2009143389). Asolution of IM1 (284 mg, 1.12 mmol) and dimethylamine (1.23 mmol, 1.1mL, 40% in water) in THF-H₂O (1:1,4 mL) was stirred at 80° C. overnight.HPLC showed full conversion. The reaction mixture was concentrated underreduced pressure followed by partition between saturated sodiumbicarbonate solution and DCM. Upon extraction the combined DCM extractswere dried over anhydrous sodium sulfate. The solvents were removed togive IM2 as yellow viscous oil (315 mg). No further purification wasperformed.

IM2 (315 mg) was reduced into IM3 using standard Zn/NH₄Cl proceduredescribed previously; a pale yellow oil was obtained (308 mg). Thiscrude material was used directly in the next step.

IM4 was prepared according to a literature procedure (Nature 2009, 462,1070). This material (400 mg) underwent a S_(N)Ar reaction with IM3 (308mg) under standard condition (TFA, 2-BuOH, 100° C., overnight).Conventional workup followed by flash chromatography on silica gel(eluent: 0-15% MeOH in DCM) afforded IM5 as a white foam (89 mg, 15%).

IM5 (26 mg) was converted into corresponding acrylamide under standardacroylation procedure described previously. Conventional workup followedby preparative TLC (eluent: 10% MeOH in DCM) afforded the desiredproduct as a light yellow solid (20 mg, 77%).

Compounds of the Invention

The compounds depicted below were synthesized using methods describedherein or by methods analogous thereto and can be useful for treatingEGFR-driven cancers.

Examples 1-21 were made in accordance with the methods shown in Scheme24 by substituting appropriate alcohols for1-(2-hydroxyethyl)-4-methylpiperazine.

Example 1N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-(2-(pyrrolidin-1-yl)ethoxy)phenyl)acrylamide

Example 2N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)acrylamide

Example 3N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-((1-methylpiperidin-4-yl)methoxy)phenyl)acrylamide

Example 4N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-(2-morpholinoethoxyl)phenyl)acrylamide

Example 5N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-(3-morpholinopropoxy)phenyl)acrylamide

Example 6N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)acrylamide

Example 7N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-((1-methylpiperidin-2-yl)methoxy)phenyl)acrylamide

Example 8N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-(2-(piperidin-1-yl)ethoxy)phenyl)acrylamide

Example 9N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-(oxetan-3-yloxy)phenyl)acrylamide

Example 10N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-(pyridin-3-ylmethoxy)phenyl)acrylamide

Example 11N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-(pyridin-4-ylmethoxy)phenyl)acrylamide

Example 12N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-((1-methylpiperidin-3-yl)oxy)phenyl)acrylamide

Example 13N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-((1-methylpyrrolidin-3-yl)oxy)phenyl)acrylamide

Example 14rel-(R)—N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-((1-methylpiperidin-3-yl)oxy)phenyl)acrylamide

Example 15N-(2-((1-(azetidin-1-yl)-3-methoxypropan-2-yl)oxy)-5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide

Example 16rel-(R)—N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-((1-methylpiperidin-3-yl)oxy)phenyl)acrylamide

Example 17N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-((1-methylazetidin-3-yl)oxy)phenyl)acrylamide

Example 18N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-((1-methylpyrrolidin-2-yl)methoxy)phenyl)acrylamide

Example 19N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-((4-methyl-1,4-oxazepan-6-yl)oxy)phenyl)acrylamide

Example 20N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-((1-methylpyrrolidin-3-yl)methoxy)phenyl)acrylamide

Example 21N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)cyclohexyl)oxy)-4-methoxyphenyl)acrylamide

Examples 22-32 were made in accordance with the methods shown in Scheme25.

Example 22N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)acrylamide

Example 23N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(4-(dimethylamino)piperidin-1-yl)-4-methoxyphenyl)acrylamide

Example 24N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(3-(dimethylamino)pyrrolidin-1-yl)-4-methoxyphenyl)acrylamide

Example 25N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-(4-methyl-1,4-diazepan-1-yl)phenyl)acrylamide

Example 26rac-(R)—N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(3-(dimethylamino)pyrrolidin-1-yl)-4-methoxyphenyl)acrylamide

N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-(4-(1methylpiperidin-4yl)piperazin-1yl)acrylamide

Example 28N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-(3-morpholinopyrrolidin-1-yl)phenyl)acrylamide

Example 29rac-(R)—N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(3-(dimethylamino)pyrrolidin-1-yl)-4-methoxyphenyl)acrylamide

Example 30N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(3-(dimethylamino)piperidin-1-yl)-4-methoxyphenyl)acrylamide

Example 31N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-(3-(pyrrolidin-1-yl)azetidin-1-yl)phenyl)acrylamide

Example 32N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(3-hydroxypyrrolidin-1-yl)-4-methoxyphenyl)acrylamide

Examples 33-41 were made in accordance with the methods shown in Scheme26 by substituting secondary amines for (3-dimethylamino)pyrrolidine.

Example 33N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-(3-(piperidin-1-yl)pyrrolidin-1-yl)phenyl)acrylamide

Example 34N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(3-(diethylamino)pyrrolidin-1-yl)-4-methoxyphenyl)acrylamide

Example 35N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(3-hydroxy-[1,3′-bipyrrolidin]-1′-yl)-4-methoxyphenyl)acrylamide

Example 36N-(2-([1,3′-bipyrrolidin]-1′-yl)-5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide

Example 37N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-(3-(4-methylpiperazin-1yl)pyrrolidin-1-yl)phenyl)acrylamide

Example 38N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(3-((2-(diethylamino)ethyl)(methyl)amino)pyrrolidin-1-yl)-4-methoxyphenyl)acrylamide

Example 39N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(3-(4-hydroxypiperidin-1-yl)pyrrolidin-1-yl)-4-methoxyphenyl)acrylamide

Example 40N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(3-(4-(2-hydroxyethyl)piperazin-1-yl)pyrrolidin-1-yl)-4-methoxyphenyl)acrylamide

Example 41N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-(3-((2-methoxyethyl)(methyl)amino)pyrrolidin-1-yl)phenyl)acrylamide

Examples 42-53 were made in accordance with the methods shown in Scheme27.

Example 42N-(3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)-2-(pyrrolidin-1-ylmethyl)acrylamide

Example 43N-(3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)-2-(piperidin-1-ylmethyl)acrylamide

Example 44N-(3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)-2-((4-(methylsulfonyl)piperazin-1-yl)methyl)acrylamide

Example 45N-(3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)-2-((4-(4-methylpiperazin-1-yl)piperidin-1-yl)methyl)acrylamide

Example 46N-(3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)-2-((1,1-dioxidothiomorpholino)methyl)acrylamide

Example 47N-(3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)-2-((3-oxopiperazin-1-yl)methyl)acrylamide

Example 48N-(3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)-2-(morpholinomethyl)acrylamide

Example 49N-(3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)-2-((4-methylpiperazin-1-yl)methyl)acrylamide

Example 50N-(3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)-2-((4-isopropylpiperazin-1-yl)methyl)acrylamide

Example 51N-(3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)-2-((4-morpholinopiperidin-1-yl)methyl)acrylamide

Example 52N-(3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)-2-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)acrylamide

Example 53N-(3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)-2-((3-hydroxypyrrolidin-1-yl)methyl)acrylamide

Example 54 was made in accordance with the methods shown in Scheme 28.

Example 54N-(3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-fluorophenyl)acrylamide

Examples 55-57 were made in accordance with the methods shown in Scheme29.

Example 55N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-((4-methylpiperazin-1-yl)methyl)phenyl)acrylamide

Example 56N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-(4-methylpiperazine-1-carbonyl)phenyl)acrylamide

Example 57 was made in accordance with the methods shown in Scheme 30.

Example 57N-(2-(3-aminopyrrolidin-1-yl)-5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide

Examples 58-64 were made in accordance with the methods shown in Scheme31.

Example 58N1-(3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)-N4-(2-(dimethylamino)ethyl)fumaramide

Example 59(E)-N-(3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)-4-(4-methylpiperazin-1-yl)-4-oxobut-2-enamide

Example 60N1-(3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)-N4,N4-dimethylfumaramide

Example 61(Z)-4-((3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)amino)-4-oxobut-2-enoicacid

Example 62N1-(3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)-N4,N4-dimethylmaleamide

Example 63(Z)—N-(3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)-4-(4-methylpiperazin-1-yl)-4-oxobut-2-enamide

Example 64N1-(3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)-N4-(2-(dimethylamino)ethyl)maleamide

Example 65 was made in accordance with the methods shown in Scheme 32.

Example 65N-(2-(3-amino-3-methylbut-1-yn-1-yl)-5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide

Example 66 was made in accordance with the methods shown in Scheme 33.

Example 66N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(2-(dimethylamino)-3-hydroxypropoxy)-4-methoxyphenyl)acrylamide

Example 67 was made in accordance with the methods shown in Scheme 35.

Example 67N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-((2-((2-fluoroethyl)(methyl)amino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide

Examples 68-73 were made in accordance with the methods shown in Scheme37.

Example 68N-(2-(3-(azetidin-1-yl)pyrrolidin-1-yl)-5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide

Example 69N-(2-([1,4′-bipiperidin]-1′-yl)-5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide

Example 70N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-(4-morpholinopiperidin-1-yl)phenyl)acrylamide

Example 71N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-(4-(4-methyl-1,4-diazepan-1-yl)piperidin-1-yl)phenyl)acrylamide

Example 72N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-(4-(pyrrolidin-1-yl)piperidin-1-yl)phenyl)acrylamide

Example 73 was made in accordance with the methods shown in Scheme 38.

Example 73N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-((1-(dimethylamino)cyclopropyl)ethynyl)-4-methoxyphenyl)acrylamide

Example 74 was made in accordance with the methods shown in Scheme 40.

Example 74N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-(2-(4-methylpiperazin-1-yl)ethyl)phenyl)acrylamide

Example 75 was made in accordance with the methods shown in Scheme 41.

Example 75 (E)-ethyl4-((3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)amino)-4-oxobut-2-enoate

Example 76 was made in accordance with the methods shown in Scheme 42.

Example 76 (E)-tert-butyl(1-(3-((3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)amino)-3-oxoprop-1-en-1-yl)cyclopropyl)carbamate

Example 77N-(3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)-2-fluoroacrylamide

Example 78(E)-3-chloro-N-(3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide

Example 79N-(3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)cyclohex-1-enecarboxamide

Example 80N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-(2-(pyrrolidin-1-yl)ethoxy)phenyl)but-2-ynamide

Example 81N-(3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)-4-(dimethylamino)but-2-ynamide

Example 82N-(3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)-2-(trifluoromethyl)acrylamide

Example 83N-(3-((5-chloro-2-((4-(dimethylphosphoryl)-2-methoxyphenyl)amino)pyrimidin-4-yl)oxy)phenyl)-4-(dimethylamino)but-2-ynamide

Example 84N-(3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)-1-methyl-1,2,5,6-tetrahydropyridine-3-carboxamide

Example 85(E)-3-chloro-N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-fluoro-4-methoxyphenyl)acrylamide

Example 86N-(3-((5-chloro-4-((2-(dimethylphosphoryl)-4-(2-methoxyethoxyl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide

Example 87N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-fluoro-4-methoxyphenyl)-4-(dimethylamino)but-2-ynamide

Example 88N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-fluoro-4-methoxyphenyl)-5-(piperidin-1-yl)pent-2-ynamide

Example 89N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-fluoro-4-methoxyphenyl)-4-(pyrrolidin-1-yl)but-2-ynamide

Example 90N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-fluoro-4-methoxyphenyl)-4-methyl-4-(pyrrolidin-1-yl)pent-2-ynamide

Example 91N-(3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)-4-methyl-4-(pyrrolidin-1-yl)pent-2-ynamide

Example 92(E)-N-(3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)-4-(piperidin-1-yl)but-2-enamide

Example 93N-(3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)-3-phenylpropiolamide

Example 94(E)-3-(1-aminocyclopropyl)-N-(3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide

Example 95(E)-N-(3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)-4-(pyrrolidin-1-yl)but-2-enamide

Example 96N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(3-(diethylamino)prop-1-yn-1-yl)-4-methoxyphenyl)acrylamide

Example 97N-(3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)-4-methoxybut-2-ynamide

Example 98N-(5-((5-chloro-4-((2-(dimethylphosphoryl)-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)amino)pyrimidin-2-yl)amino)-2-fluoro-4-methoxyphenyl)acrylamide

Example 99N-(3-((5-chloro-4-((2-(dimethylphosphoryl)-4-((tetrahydrofuran-3-yl)oxy)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide

Example 100N-(3-((5-chloro-4-((2-(dimethylphosphoryl)-4-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide

Example 101N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-morpholinophenyl)-5-(piperidin-1-yl)pent-2-ynamide

Example 102N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)but-2-ynamide

Example 103N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-(oxetan-3-yloxy)phenyl)but-2-ynamide

Example 104N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-morpholinophenyl)-4-(dimethylamino)but-2-ynamide

Example 105N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-morpholinophenyl)-4-methoxybut-2-ynamide

Example 106N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)but-2-ynamide

Example 107N-(4-((5-chloro-4-((2-(dimethylphosphoryl)-3-(2-(piperidin-1-yl)ethoxy)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)acrylamide

Example 108N-(3-((5-chloro-4-((2-(dimethylphosphoryl)-4-(2-(piperidin-1-yl)ethoxy)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide

Example 109N1-(3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)-N4-methylfumaramide

Example 110N1-(3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)-N4-methylmaleamide

Example 111N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(3-(dimethylamino)pyrrolidin-1-yl)-4-methoxyphenyl)-4-methoxybut-2-ynamide

Example 112N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(3-(dimethylamino)pyrrolidin-1-yl)-4-methoxyphenyl)but-2-ynamide

Example 113rac-(R)—N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(3-(dimethylamino)pyrrolidin-1-yl)-4-methoxyphenyl)methacrylamide

Example 114N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-morpholinophenyl)-5-(dimethylamino)pent-2-ynamide

Example 115N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-morpholinophenyl)-5-methoxypent-2ynamide

Example 116N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-(3-methyl-3-(pyrrolidin-1-yl)but-1-yn-1-yl)phenyl)acrylamide

Example 117N-(3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-(2-(dimethylamino)ethoxy)phenyl)acrylamide

Example 118N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-morpholinophenyl)-5-(4-methylpiperazin-1-yl)pent-2-ynamide

Example 119N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-(pyrrolidin-1-yl)phenyl)-5-(4-methylpiperazin-1-yl)pent-2-ynamide

Example 120N-(5-((5-cyclopropyl-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-((2-(diethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide

Example 121N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-((1-(diethylamino)-3-fluoropropan-2-yl)oxy)-4-methoxyphenyl)acrylamide

Example 122N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-morpholinophenyl)-5-(2-(methoxymethyl)pyrrolidin-1-yl)pent-2-ynamide

Example 123N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-((1-(2-methoxyethyl)piperidin-3-yl)oxy)phenyl)acrylamide

Example 124N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(3-(dimethylamino)prop-1-yn-1-yl)-4-methoxyphenyl)acrylamide

Example 125N-(3-((5-chloro-4-((4-(2-(dimethylamino)ethoxy)-2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide

Example 126N-(3-((5-chloro-4-((4-(3-(dimethylamino)propoxy)-2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide

Example 1271-(6-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-5-methoxyindolin-1-yl)prop-2-en-1-one

Example 128

N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pryimidin-2-yl)amino)-2-(4-dimethylamino)but-1-yn-1-yl)-4-methoxyphenyl)acrylamideExample 129

(R)—N-(5((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pryimidin-2-yl)amino)-2-((1-(dimethylamino)-3-methoxypropan-2-yl)oxy)-4-methoxyphenyl)acrylamide

Example 130N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-((1-dimethylamino)-3methoxypropan-2-yl)oxy)-4-methoxyphenyl)acrylamide Example 131

N-(3-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-methoxypyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide

Example 1322-chloro-N-(3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide

Example 133N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-methylphenyl)acrylamideExample 134

N-(3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-(trifluoromethoxy)phenyl)acrylamideExample 135

N-(3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pryimidin-2-yl)amino)-4-ethylphenyl)acrylamideExample 136

N-(4-chloro-3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pryimidin-2-yl)amino)phenyl)acrylamideExample 137

2-chloro-N-(3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)acetamideExample 138

N-(3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-(oxetan-3-yloxy)phenyl)acrylamideExample 139

N-(3-((5-cyano-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamideExample 140

2-chloro-N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-methylphenyl)acetamideExample 141

2-chloro-N-(3-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-methylpyrimidin-2-yl)amino)-4-methoxyphenyl)acetamideExample 142

N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pryimidin-2-yl)amino)-2-((1-(dimethylamino)-3-ethoxypropan-2-yl)oxy)-4-methoxyphenyl)acrylamideExample 143

N-5-((5-cloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-yl)amino)-2-((1-(dimethylamino)-3-methoxypropan-2-yl)oxy)-4-methylphenyl)acrylamideExample 144

N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-((1-(dimethylamino)-3-methoxypropan-2-yl)oxy)-4-methylphenyl)acrylamide

N-(4-chloro-5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-((1-(dimethylamino)-3-methoxypropan-2-yl)oxy)phenyl)acrylamideExample 146

N-(4-chloro-5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-((1-(dimethylamino)-3-methoxypropan-2-yl)oxy)phenyl)acrylamide

Example 147N-(3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)-2-fluoroacetamide

Example 1482-chloro-N-(3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methylphenyl)acetamideExample 1492-chloro-N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-fluoro-4-methoxyphenyl)acetamide

Example 1501-chloro-N-(3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)methanesulfonamide

Example 151

N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(3-(dimethylamino)prop-1-yn-1-yl)-4-methylphenyl)acrylamideExample 152

N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(3-(dimethylamino)prop-1-yn-1-yl)-4-ethylphenyl)acrylamideExample 153

N-(5-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-2-(3-(dimethylamino)prop-1-yn1-yl)-4-methoxyphenyl)acrylamide Example 154

N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(3-(diethylamino)-3-methylbut-1-yn-1-yl)-4-methoxyphenyl)acrylamideExample 155

N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(3-(dimethylamio)-3-methylbut-1-yn-1-yl)-4-methoxyphenyl)acrylamideExample 156

N-(4-chloro-5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(3-(dimethylamino)prop-1-yn-1-yl)phenyl)acrylamideExample 157

N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methyoxy-2-(3-(pyrrolidin-1-yl)prop-1-yn-1-yl)phenyl)acrylamide Example 158

N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(3-(diisopropylamino)prop-1-yn-1-yl)-4-methoxyphenyl)acrylamideExample 159

N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-(3-(4-methylpiperazin-1-yl)prop-1-yn-1-yl)phenyl)acrylamideExample 160

N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-(3-(methylamino)prop-1-yn-1-yl)phenyl)acrylamideExample 161

N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-(3-((2-methoxyethyl)(methyl)amino)prop-1-yn-1-yl)phenyl)acrylamideExample 162

N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(3-(ethyl(methyl)amino)prop-1-yn-1-yl)-4-methoxyphenyl)acrylamideExample 163

N-(3-((6-((3-(dimethylphosphoryl)pyridin-2-yl)amino)pyrimidin-4-yl)amino)-4-methoxyphenyl)acrylamideExample 164

N-(3-((5-chloro-4-((4-(dimethylphosphoryl)pyridin-3-yl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamideExample 165

N-(2-(3-(azepan-1-yl)prop-1-yn-1-yl)-5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamideExample 166

N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(3-(isopropyl(methyl)amino)prop-1-yn-1-yl)-4-methoxyphenyl)acrylamideExample 167

N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methyoxy-2-(3-(piperidin-1-yl)prop-1-yn-1-yl)phenyl)acrylamideExample 168

N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(3-(cyclopentyl(methyl)amino)prop-1-yn-1-yl)-4-methoxyphenyl)acrylamide

Example 169N-(3-((4-((2-(dimethylphosphoryl)phenyl)amino)-1,3,5-triazin-2-yl)amino)-4-methoxyphenyl)acrylamideExample 170

N-(3-((4-((2-(dimethylphosphoryl)phenyl)amino)-1,3,5-triazin-2-yl)amino)-4-(trifluoromethoxy)phenyl)acrylamide Example 171

N-(3-((6-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-4-yl)amino)-4-methoxyphenyl)acrylamideExample 172

(1S,2R,3S,4R)-3-((2-((5-acrylamido-2-methoxyphenyl)amino)-5-chloropyrimidin-4-yl)amino)bicyclo[2.2.1]heptane-2-carboxamideExample 173

2-((2-((5-acrylamido-4-(3-(dimethylamino)pyrrolidin-1-yl)-2-methoxyphenyl)amino)-5-chloropyrimidin-4-yl)amino)benzamideExample 174

N-(5-((5-chloro-4-((2-cyanophenyl)amino)pyrimidin-2-yl)amino)-2-(3-(dimethylamino)pyrrolidin-1-yl)-4-methoxyphenyl)acrylamideExample 175

N-(5-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-2-(3-(dimethylamino)pyrrolidin-1-yl)-4-methoxyphenyl)acrylamideExample 176

N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)methyl)-4-methoxy-2-(3-(4-methylpiperidin-1-yl)prop-1-yn-1-yl)phenyl)acrylamideExample 177

N-(2-(3-(tert-butyl(methyl)amino)prop-1-yn-1-yl)-5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl) methyl)-4-methoxyphenyl)acrylamide

Example 178

N-(5-((5-chloro-4-((2-(dimethylphosphoryl) phenyl)amino)pyrimidin-2-yl)methyl)-2-(3-(2-(dimethylamino)pyrrolidin-1-yl)prop-1-yn-1-yl)-4-methoxyphenyl)acrylamide

Example 179

N-(5-((5-chloro-4-((2-(dimethylphosphoryl) phenyl)amino)pyrimidin-2-yl)methyl)-4-methoxy-2-(3-(2-methylpiperidin-1-yl)prop-1-yn-1-1-yl)phenyl)acrylamide

Example 180

(Z)-N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl) methyl)-2-(3-(dimethylamino)prop-1-en-1-yl)4-methoxyphenyl)acrylamide

Example 181

(E)-N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl) methyl)-2-(3-(dimethylamino)prop-1-en-1-yl)4-methoxyphenyl)acrylamide

Example 182

N-(5-((5-chloro-4-((2-(dimethylphosphoryl) phenyl)amino)pyrimidin-2-yl)methyl)-2-(3-(4-fluoropiperidin-1-yl)prop-1-yn-1-yl)-4-methoxyphenyl)acrylamide

Example 183

N-(5-((5-chloro-4-((2-(dimethylphosphoryl) phenyl)amino)pyrimidin-2-yl)methyl)-4-methoxy-2-(3-(methyl(tetrahydro-2H-pyran-4-yl)amino)prop-1-yn-1-yl)phenyl)acrylamide

Example 184

N-(5-((5-chloro-4-((2-(dimethylphosphoryl) phenyl)amino)pyrimidin-2-yl)methyl)-4-methoxy-2-(3-(dimethylamino)prop-1-yn-1-yl)4-methoxyphenyl)but-2-ynamide

Example 185

N-(3-((5-chloro-2-(2-methoxy-4-(1-methyl-4-oxido-1,4-azaphosphinan-4-yl)benzyl)pyrimidin-4-yl)oxy)phenyl)acrylamide

Example 186 Additional Compounds of the Invention

The compounds depicted below can be synthesized using methods analogousto those described herein and can be useful for treating EGFR-drivencancers.

Biological Assays.

Kinase inhibitory activity of the compounds was measured against humanEGFR (native sequence) and against EGFR bearing the L858R mution and theL858R/T790M double mutation (EGFR, L858R, and L858R/T790M, respectivelyin Table 1). Additional assays can be conducted with EGFR deletionmutants such as delE746-A750 with or without the additional T790Mmutation. Assay conditions included 10 pt curves with 3 μM topconcentration (singlicates) and 10 μM ATP.

We also assessed the antiproliferative activity of compounds of Formula(I) against BaF3 cells expressing the target EGFR mutations or control(i.e., cell lines expressing wildtype EGFR). Assays were conducted usingMTT.

TABLE 1 IC50 for kinase inhibition (nM)¹ BAF3 BAF3 EGFR EGFR DEL L858R-EGFR T790M T790M Example Chemical Name LC-MS EGFR L858R BAF3 PURO PURO #(ChemDraw Ultra 12.0 (M + H) EGFR L858R T790M PARENTAL POOL POOL 1N-(5-((5-chloro-4-((2- 585.2 A A A D A A(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-(2-(pyrrolidin-1- yl)ethoxy)phenyl)acrylamide 2N-(5-((5-chloro-4-((2- 614.2 C A A D D N/A(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)acrylamide 3 N-(5-((5-chloro-4-((2- 599.2 B A A D C D(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-((1-methylpiperidin-4-yl)methoxy)phenyl)acrylamide 4 N-(5-((5-chloro-4-((2- 601.2 A A A D B C(dimethylphosphoryl)phenyl)amino)pyrimidin-2- yl)amino)-4-methoxy-2-(2-morpholinoethoxy)phenyl)acrylamide 5 N-(5-((5-chloro-4-((2- 615.2 C A AD C C (dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-(3- morpholinopropoxy)phenyl)acrylamide 6N-(5-((5-chloro-4-((2- 586.2 D A B D B C(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)acrylamide 7 N-(5-((5-chloro-4-((2- 599.2 A A A D A A(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-((1-methylpiperidin-2-yl)methoxy)phenyl)acrylamide 8 N-(5-((5-chloro-4-((2- 599.2 A A A D A A(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-(2-(piperidin-1- yl)ethoxy)phenyl)acrylamide 9N-(5-((5-chloro-4-((2- 544.1 D A A D A B(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-(oxetan-3- yloxy)phenyl)acrylamide 10N-(5-((5-chloro-4-((2- 579.2 B A A D B C(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-(pyridin-3- ylmethoxy)phenyl)acrylamide 11N-(5-((5-chloro-4-((2- 579.1 A A A D A C(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-(pyridin-4- ylmethoxy)phenyl)acrylamide 12N-(5-((5-chloro-4-((2- 585.2 A A A D A A(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-((1-methylpiperidin-3- yl)oxy)phenyl)acrylamide 13N-(5-((5-chloro-4-((2- 571.2 A A A D A A(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-((1-methylpyrrolidin-3- yl)oxy)phenyl)acrylamide14 rel-(R)-N-(5-((5-chloro-4-((2- 585.2 A A A D A A(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-((1-methylpiperidin-3- yl)oxy)phenyl)acrylamide 15N-(2-((1-(azetidin-1-yl)-3-methoxypropan-2-yl)oxy)-5-((5- 615.2 A A A DA A chloro-4-((2- (dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide 16 rel-(R)-N-(5-((5-chloro-4-((2-585.2 A A A D A A (dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-((1-methylpiperidin-3- yl)oxy)phenyl)acrylamide 17N-(5-((5-chloro-4-((2- 557.2 N/A N/A N/A D B C(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-((1-methylazetidin-3- yl)oxy)phenyl)acrylamide 18N-(5-((5-chloro-4-((2- 585.2 N/A N/A N/A D A A(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-((1-methylpyrrolidin-2-yl)methoxy)phenyl)acrylamide 19 N-(5-((5-chloro-4-((2- 601.2 N/A N/A N/AN/A N/A N/A (dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-((4-methyl-1,4-oxazepan-6-yl)oxy)phenyl)acrylamide 20 N-(5-((5-chloro-4-((2- 585.2 N/A N/A N/A N/AN/A N/A (dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-((1-methylpyrrolidin-3-yl)methoxy)phenyl)acrylamide 21 N-(5-((5-chloro-4-((2- 613.2 N/A N/A N/AN/A N/A N/A (dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)cyclohexyl)oxy)-4-methoxyphenyl)acrylamide 22 N-(5-((5-chloro-4-((2- 653.2 A A A D B B(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)acrylamide 23 N-(5-((5-chloro-4-((2- 598.2 A AA D A C (dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(4-(dimethylamino)piperidin-1-yl)-4-methoxyphenyl)acrylamide 24 N-(5-((5-chloro-4-((2- 584.2 A A A D A A(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(3-(dimethylamino)pyrrolidin-1-yl)-4-methoxyphenyl)acrylamide 25 N-(5-((5-chloro-4-((2- 584.2 A A A D A A(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-(4-methyl-1,4-diazepan-1- yl)phenyl)acrylamide 26rac-(R)-N-(5-((5-chloro-4-((2- 584.2 A A A D A A(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(3-(dimethylamino)pyrrolidin-1-yl)-4-methoxyphenyl)acrylamide 27 N-(5-((5-chloro-4-((2- 653.3 A A A D B C(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)phenyl)acrylamide 28 N-(5-((5-chloro-4-((2- 626.2 A AA D A A (dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-(3-morpholinopyrrolidin-1- yl)phenyl)acrylamide 29rac-(R)-N-(5-((5-chloro-4-((2- 584.2 A A A D A A(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(3-(dimethylamino)pyrrolidin-1-yl)-4-methoxyphenyl)acrylamide 30 N-(5-((5-chloro-4-((2- 598.2 A A A D A A(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(3-(dimethylamino)piperidin-1-yl)-4-methoxyphenyl)acrylamide 31 N-(5-((5-chloro-4-((2- 596.2 A A A D A A(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-(3-(pyrrolidin-1-yl)azetidin-1-yl)phenyl)acrylamide 32 N-(5-((5-chloro-4-((2- 557.2 A A A D B C(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(3-hydroxypyrrolidin-1-yl)-4- methoxyphenyl)acrylamide 33N-(5-((5-chloro-4-((2- 624.3 A A A D A A(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-(3-(piperidin-1-yl)pyrrolidin-1-yl)phenyl)acrylamide 34 N-(5-((5-chloro-4-((2- 612.2 A A A D A A(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(3-(diethylamino)pyrrolidin-1-yl)-4-methoxyphenyl)acrylamide 35 N-(5-((5-chloro-4-((2- 626.2 A A A D C D(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(3-hydroxy-[1,3′-bipyrrolidin]-1′-yl)-4-methoxyphenyl)acrylamide 36N-(2-([1,3′-bipyrrolidin]-1′-yl)-5-((5-chloro-4-((2- 610.2 A A A D A A(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide 37 N-(5-((5-chloro-4-((2- 639.3 A AA D B C (dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-(3-(4-methylpiperazin-1-yl)pyrrolidin-1-yl)phenyl)acrylamide 38 N-(5-((5-chloro-4-((2- 669.3 A AA D A C (dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(3-((2-(diethylamino)ethyl)(methyl)amino)pyrrolidin-1-yl)-4-methoxyphenyl)acrylamide 39 N-(5-((5-chloro-4-((2- 640.3 A A A D C D(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(3-(4-hydroxypiperidin-1-yl)pyrrolidin-1-yl)-4-methoxyphenyl)acrylamide 40 N-(5-((5-chloro-4-((2- 669.2 A A A D D D(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(3-(4-(2-hydroxyethyl)piperazin-1-yl)pyrrolidin-1-yl)-4-methoxyphenyl)acrylamide 41 N-(5-((5-chloro-4-((2-628.2 A A A D A A (dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-(3-((2- methoxyethyl)(methyl)amino)pyrrolidin-1-yl)phenyl)acrylamide 42 N-(3-((5-chloro-4-((2- 555.2 A A A D A A(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)-2-(pyrrolidin-1- ylmethyl)acrylamide 43N-(3-((5-chloro-4-((2- 569.2 A A A D A A(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)-2-(piperidin-1- ylmethyl)acrylamide 44N-(3-((5-chloro-4-((2- 648.1 A A A D A A(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)-2-((4-(methylsulfonyl)piperazin-1-yl)methyl)acrylamide 45N-(3-((5-chloro-4-((2- 667.3 A A A D A A(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)-2-((4-(4-methylpiperazin-1-yl)piperidin-1-yl)methyl)acrylamide 46 N-(3-((5-chloro-4-((2- 619.1 D BA D D D (dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)-2-((1,1-dioxidothiomorpholino)methyl)acrylamide 47 N-(3-((5-chloro-4-((2- 584.2A A A D C D (dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)-2-((3-oxopiperazin-1- yl)methyl)acrylamide 48N-(3-((5-chloro-4-((2- 571.2 A A A D A A(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)-2- (morpholinomethyl)acrylamide 49N-(3-((5-chloro-4-((2- 584.2 A A A D A A(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)-2-((4-methylpiperazin-1- yl)methyl)acrylamide50 N-(3-((5-chloro-4-((2- 612.2 B A A D A A(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)-2-((4-isopropylpiperazin-1-yl)methyl)acrylamide 51 N-(3-((5-chloro-4-((2- 654.3 A A A D A A(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)-2-((4-morpholinopiperidin-1-yl)methyl)acrylamide 52 N-(3-((5-chloro-4-((2- 614.2 A A A D A A(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)-2-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)acrylamide 53 N-(3-((5-chloro-4-((2-571.2 A A A D A A (dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)-2-((3-hydroxypyrrolidin-1-yl)methyl)acrylamide 54 N-(3-((5-chloro-4-((2- 460.1 N/A N/A N/A D A A(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-fluorophenyl)acrylamide 55 N-(5-((5-chloro-4-((2- 584.2 A AA D A B (dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-((4-methylpiperazin-1- yl)methyl)phenyl)acrylamide56 N-(5-((5-chloro-4-((2- 598.2 C A A D D D(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-(4-methylpiperazine-1- carbonyl)phenyl)acrylamide57 N-(2-(3-aminopyrrolidin-1-yl)-5-((5-chloro-4-((2- 556.2 A A A D D D(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide 58 N1-(3-((5-chloro-4-((2- 586.2 AA A D D D (dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)-N4-(2- (dimethylamino)ethyl)fumaramide 59(E)-N-(3-((5-chloro-4-((2- 598.2 A A A D C D(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)-4-(4-methylpiperazin-1-yl)-4-oxobut-2-enamide 60 N1-(3-((5-chloro-4-((2- 543.2 D B C D D D(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)-N4,N4-dimethylfumaramide 61(Z)-4-((3-((5-chloro-4-((2- 516.1 D D C D D D(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)amino)-4-oxobut-2-enoic acid 62N1-(3-((5-chloro-4-((2- 543.2 D D D D D D(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)-N4,N4-dimethylmaleamide 63(Z)-N-(3-((5-chloro-4-((2- 598.2 D C D D D D(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)-4-(4-methylpiperazin-1-yl)-4-oxobut-2-enamide 64 N1-(3-((5-chloro-4-((2- 586.2 D A A D D D(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)-N4-(2- (dimethylamino)ethyl)maleamide 65N-(2-(3-amino-3-methylbut-1-yn-1-yl)-5-((5-chloro-4-((2- 553.2 A A A D AA (dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide 66 N-(5-((5-chloro-4-((2- 589.2 N/AN/A N/A D C D (dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(2-(dimethylamino)-3-hydroxypropoxy)-4-methoxyphenyl)acrylamide 67 N-(5-((5-chloro-4-((2- 604.2 A A A D A A(dimethylphosphoryl)phenyl)amino)pyrimidin-2- yl)amino)-2-((2-((2-fluoroethyl)(methyl)amino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide 68N-(2-(3-(azetidin-1-yl)pyrrolidin-1-yl)-5-((5-chloro-4-((2- 596.2 A A AD A A (dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide 69N-(2-([1,4′-bipiperidin]-1′-yl)-5-((5-chloro-4-((2- 638.3 A A A D A A(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide 70 N-(5-((5-chloro-4-((2- 640.3 A AA D A A (dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-(4-morpholinopiperidin-1- yl)phenyl)acrylamide 71N-(5-((5-chloro-4-((2- 667.3 A A A D B c(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-(4-(4-methyl-1,4-diazepan-1-yl)piperidin-1-yl)phenyl)acrylamide 72 N-(5-((5-chloro-4-((2- 624.2 B AA D A C (dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-(4-(pyrrolidin-1-yl)piperidin-1-yl)phenyl)acrylamide 73 N-(5-((5-chloro-4-((2- 579.2 D A A D C C(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-((1-(dimethylamino)cyclopropyl)ethynyl)-4-methoxyphenyl)acrylamide 74 N-(5-((5-chloro-4-((2- 598.3 A A A D C D(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-(2-(4-methylpiperazin-1-yl)ethyl)phenyl)acrylamide 75 (E)-ethyl 4-((3-((5-chloro-4-((2- 544.1 AA A D A A (dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)amino)-4-oxobut-2-enoate 76(E)-tert-butyl(1-(3-((3-((5-chloro-4-((2- 627.2 D D D D D D(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)amino)-3-oxoprop-1-en-1-yl)cyclopropyl)carbamate 77 N-(3-((5-chloro-4-((2- 490.1 D A B D A B(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)-2-fluoroacrylamide 78(E)-3-chloro-N-(3-((5-chloro-4-((2- 506 A A A D A A(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide 79 N-(3-((5-chloro-4-((2- 526.2 D DD D D D (dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)cyclohex-1-enecarboxamide 80N-(5-((5-chloro-4-((2- 597.2 D A A D A C(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-(2-(pyrrolidin-1- yl)ethoxy)phenyl)but-2-ynamide81 N-(3-((5-chloro-4-((2- 527.2 A A A D A A(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)-4-(dimethylamino)but-2- ynamide 82N-(3-((5-chloro-4-((2- 540.1 A A A D D D(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)-2- (trifluoromethyl)acrylamide 83N-(3-((5-chloro-2-((4-(dimethylphosphoryl)-2- 528.2 A A A D C Dmethoxyphenyl)amino)pyrimidin-4-yl)oxy)phenyl)-4-(dimethylamino)but-2-ynamide 84 N-(3-((5-chloro-4-((2- 541.2 D A A D D D(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)-1-methyl-1,2,5,6-tetrahydropyridine-3-carboxamide 85 (E)-3-chloro-N-(5-((5-chloro-4-((2-524 A A A D A A (dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-fluoro-4-methoxyphenyl)acrylamide 86N-(3-((5-chloro-4-((2-(dimethylphosphoryl)-4-(2- 546.1 B A A D A Bmethoxyethoxy)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide 87 N-(5-((5-chloro-4-((2- 545.1 A A A C A A(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-fluoro-4-methoxyphenyl)-4- (dimethylamino)but-2-ynamide 88N-(5-((5-chloro-4-((2- 599.2 A A A D A A(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-fluoro-4-methoxyphenyl)-5-(piperidin-1- yl)pent-2-ynamide 89N-(5-((5-chloro-4-((2- 571.2 A A A D A A(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-fluoro-4-methoxyphenyl)-4-(pyrrolidin-1- yl)but-2-ynamide 90N-(5-((5-chloro-4-((2- 599.2 A A A D A A(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-fluoro-4-methoxyphenyl)-4-methyl-4-(pyrrolidin-1-yl)pent-2-ynamide 91 N-(3-((5-chloro-4-((2- 581.2 A A A DA A (dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)-4-methyl-4-(pyrrolidin-1- yl)pent-2-ynamide92 (E)-N-(3-((5-chloro-4-((2- 569.2 A A A D A A(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)-4-(piperidin-1-yl)but-2- enamide 93N-(3-((5-chloro-4-((2- 546.1 D A A D A A(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)-3-phenylpropiolamide 94(E)-3-(1-aminocyclopropyl)-N-(3-((5-chloro-4-((2- 527.1 C A A D D D(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide 95 (E)-N-(3-((5-chloro-4-((2- 555.2D A A D B D (dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)-4-(pyrrolidin-1-yl)but-2- enamide 96N-(5-((5-chloro-4-((2- 581.2 D A A D A A(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(3-(diethylamino)prop-1-yn-1-yl)-4- methoxyphenyl)acrylamide97 N-(3-((5-chloro-4-((2- 514.1 A A A D A A(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)-4-methoxybut-2-ynamide 98N-(5-((5-chloro-4-((2-(dimethylphosphoryl)-4-(2- 603.2 A A A D A A(pyrrolidin-1-yl)ethoxy)phenyl)amino)pyrimidin-2-yl)amino)-2-fluoro-4-methoxyphenyl)acrylamide 99N-(3-((5-chloro-4-((2-(dimethylphosphoryl)-4- 558.2 A A A D A B((tetrahydrofuran-3-yl)oxy)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide 100N-(3-((5-chloro-4-((2-(dimethylphosphoryl)-4- 584.2 B A A D A A((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide 101 N-(5-((5-chloro-4-((2- 666.2 A A A D A A(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-morpholinophenyl)-5-(piperidin-1-yl)pent-2-ynamide 102 N-(5-((5-chloro-4-((2- 598.2 D C D D A B(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)but-2-ynamide 103 N-(5-((5-chloro-4-((2- 556.1 D A B DA B (dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-(oxetan-3-yloxy)phenyl)but-2- ynamide 104N-(5-((5-chloro-4-((2- 612.2 A A A D A A(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-morpholinophenyl)-4- (dimethylamino)but-2-ynamide105 N-(5-((5-chloro-4-((2- 599.2 A A A D A A(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-morpholinophenyl)-4- methoxybut-2-ynamide 106N-(5-((5-chloro-4-((2- 665.2 B A A D A A(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)but-2-ynamide 107N-(4-((5-chloro-4-((2-(dimethylphosphoryl)-3-(2- 599.2 C A A D A C(piperidin-1-yl)ethoxy)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)acrylamide 108N-(3-((5-chloro-4-((2-(dimethylphosphoryl)-4-(2- 599.2 A A A D A A(piperidin-1-yl)ethoxy)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide 109 N1-(3-((5-chloro-4-((2- 529.1 DA A D B C (dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)-N4-methylfumaramide 110N1-(3-((5-chloro-4-((2- 529.1 D A A D A C(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)-N4-methylmaleamide 111 N-(5-((5-chloro-4-((2-626.2 A A A D A A (dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(3-(dimethylamino)pyrrolidin-1-yl)-4-methoxyphenyl)-4-methoxybut-2-ynamide 112 N-(5-((5-chloro-4-((2- 596.2 AA A D A B (dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(3-(dimethylamino)pyrrolidin-1-yl)-4-methoxyphenyl)but-2-ynamide 113 rac-(R)-N-(5-((5-chloro-4-((2- 598.2 C AA D A A (dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(3-(dimethylamino)pyrrolidin-1-yl)-4-methoxyphenyl)methacrylamide 114 N-(5-((5-chloro-4-((2- 626.2 A A A D AA (dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-morpholinophenyl)-5- (dimethylamino)pent-2-ynamide115 N-(5-((5-chloro-4-((2- 613.2 A A A D A A(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-morpholinophenyl)-5- methoxypent-2-ynamide 116N-(5-((5-chloro-4-((2- 607.2 B A A D A A(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-(3-methyl-3-(pyrrolidin-1-yl)but-1-yn-1-yl)phenyl)acrylamide 117 N-(3-((5-chloro-4-((2- 529.2 D D D D D D(dimethylphosphoryl)phenyl)amino)pyrimidin-2- yl)amino)-4-(2-(dimethylamino)ethoxy)phenyl)acrylamide 118 N-(5-((5-chloro-4-((2- 681.2A A A D A A (dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-morpholinophenyl)-5-(4-methylpiperazin-1-yl)pent-2-ynamide 119 N-(5-((5-chloro-4-((2- 665.2 A AA D C C (dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-(pyrrolidin-1-yl)phenyl)-5-(4-methylpiperazin-1-yl)pent-2-ynamide 120 N-(5-((5-cyclopropyl-4-((2-606.3 A A A D A A (dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-((2-(diethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide 121 N-(5-((5-chloro-4-((2- 619.2 A A A D A A(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-((1-(diethylamino)-3-fluoropropan-2-yl)oxy)-4-methoxyphenyl)acrylamide 122 N-(5-((5-chloro-4-((2- 696.3 A A A D A A(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-morpholinophenyl)-5-(2-(methoxymethyl)pyrrolidin-1-yl)pent-2-ynamide 123 N-(5-((5-chloro-4-((2-629.2 A A A D A A (dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-((1-(2-methoxyethyl)piperidin-3-yl)oxy)phenyl)acrylamide 124 N-(5-((5-chloro-4-((2- 553.2 A A A D A A(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(3-(dimethylamino)prop-1-yn-1-yl)-4-methoxyphenyl)acrylamide 125N-(3-((5-chloro-4-((4-(2-(dimethylamino)ethoxy)-2- 559.2 A A A D A A(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide 126N-(3-((5-chloro-4-((4-(3-(dimethylamino)propoxy)-2- 573.2 A A A D A A(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide 127 1-(6-((5-chloro-4-((2- 498.1N/A N/A N/A D C D (dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-5-methoxyindolin-1-yl)prop-2-en-1-one 128N-(5-((5-chloro-4-((2- 567.2 A A A D A A(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(4-(dimethylamino)but-1-yn-1-yl)-4- methoxyphenyl)acrylamide129 (R)-N-(5-((5-chloro-4-((2- 603.2 A A A D A A(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-((1-(dimethylamino)-3-methoxypropan-2-yl)oxy)-4-methoxyphenyl)acrylamide 130 N-(5-((5-chloro-4-((2- 603.2 A AA D A A (dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-((1-(dimethylamino)-3-methoxypropan-2-yl)oxy)-4-methoxyphenyl)acrylamide 131N-(3-((4-((2-(dimethylphosphoryl)phenyl)amino)-5- 468.1 B A A D A Bmethoxypyrimidin-2-yl)amino)-4- methoxyphenyl)acrylamide 1322-chloro-N-(3-((5-chloro-4-((2- 506.1 A A A D A C(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide 133 N-(5-((5-chloro-4-((2- 486.1 AA A D A A (dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-methylphenyl)acrylamide 134 N-(3-((5-chloro-4-((2-526.1 A A A D A A (dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-(trifluoromethoxy)phenyl)acrylamide 135N-(3-((5-chloro-4-((2- 470.1 A A A D A A(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-ethylphenyl)acrylamide 136 N-(4-chloro-3-((5-chloro-4-((2-476 A A A D A A (dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)phenyl)acrylamide 137 2-chloro-N-(3-((5-chloro-4-((2- 514.1 A AA D A A (dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)acetamide 138 N-(3-((5-chloro-4-((2- 463.1 D DD D D D (dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-(oxetan-3-yloxy)phenyl)acrylamide 139 N-(3-((5-cyano-4-((2-508.1 A A A D C D (dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide 140 2-chloro-N-(5-((5-chloro-4-((2-474.1 A A A D A A (dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-methylphenyl)acetamide 141 2-chloro-N-(3-((4-((2-617.2 A A A D A A (dimethylphosphoryl)phenyl)amino)-5-methylpyrimidin-2-yl)amino)-4-methoxyphenyl)acetamide 142 N-(5-((5-chloro-4-((2- 587.2 AA A D A A (dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-((1-(dimethylamino)-3-ethoxypropan-2-yl)oxy)-4-methoxyphenyl)acrylamide 143 N-(5-((5-chloro-4-((2- 587.2 A AA D A A (dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-((1-(dimethylamino)-3-methoxypropan-2-yl)oxy)-4-methylphenyl)acrylamide 144 N-(5-((5-chloro-4-((2- 607.1 A A AD A A (dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-((1-(dimethylamino)-3-methoxypropan-2-yl)oxy)-4-methylphenyl)acrylamide 145 N-(4-chloro-5-((5-chloro-4-((2-606.7 A A A D A A (dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-((1-(dimethylamino)-3-methoxypropan-2-yl)oxy)phenyl)acrylamide 146 N-(4-chloro-5-((5-chloro-4-((2- 514.1 A A AD A A (dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-((1-(dimethylamino)-3-methoxypropan-2-yl)oxy)phenyl)acrylamide 147 N-(3-((5-chloro-4-((2- 478.1 D B C D D D(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)-2-fluoroacetamide 1482-chloro-N-(3-((5-chloro-4-((2- 478.1 A A A D A A(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methylphenyl)acetamide 149 2-chloro-N-(5-((5-chloro-4-((2-512.1 A A A D A A (dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-fluoro-4-methoxyphenyl)acetamide 1501-chloro-N-(3-((5-chloro-4-((2- 530.0 D D D D D D(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)methanesulfonamide 151 N-(5-((5-chloro-4-((2-537.2 A A A D A A (dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(3-(dimethylamino)prop-1-yn-1-yl)-4- methylphenyl)acrylamide152 N-(5-((5-chloro-4-((2- 551.2 A A A D A A(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(3-(dimethylamino)prop-1-yn-1-yl)-4- ethylphenyl)acrylamide153 N-(5-((5-chloro-4-((2- 583.2 A A A D A A(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-2-(3-(dimethylamino)prop-1-yn-1-yl)-4- methoxyphenyl)acrylamide 154N-(5-((5-chloro-4-((2- 536.1 A A A D A A(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(3-(diethylamino)-3-methylbut-1-yn-1-yl)-4-methoxyphenyl)acrylamide 155 N-(5-((5-chloro-4-((2- 581.2 A A A D A A(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(3-(dimethylamino)-3-methylbut-1-yn-1-yl)-4-methoxyphenyl)acrylamide 156 N-(4-chloro-5-((5-chloro-4-((2- 557.1 A AA D A A (dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(3-(dimethylamino)prop-1-yn-1- yl)phenyl)acrylamide 157N-(5-((5-chloro-4-((2- 579.2 A A A D A A(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-(3-(pyrrolidin-1-yl)prop-1-yn-1-yl)phenyl)acrylamide 158 N-(5-((5-chloro-4-((2- 609.2 A A A D A A(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(3-(diisopropylamino)prop-1-yn-1-yl)-4-methoxyphenyl)acrylamide 159 N-(5-((5-chloro-4-((2- 608.2 A A A D A C(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-(3-(4-methylpiperazin-1-yl)prop-1-yn-1-yl)phenyl)acrylamide 160 N-(5-((5-chloro-4-((2- 539.1 A A A D A A(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-(3-(methylamino)prop-1-yn-1- yl)phenyl)acrylamide161 N-(5-((5-chloro-4-((2- 597.2 A A A D A A(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-(3-((2- methoxyethyl)(methyl)amino)prop-1-yn-1-yl)phenyl)acrylamide 162 N-(5-((5-chloro-4-((2- 567.2 A A A D A A(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(3-(ethyl(methyl)amino)prop-1-yn-1-yl)-4-methoxyphenyl)acrylamide 163 N-(3-((6-((3-(dimethylphosphoryl)pyridin-2-439.1 B A C D D D yl)amino)pyrimidin-4-yl)amino)-4-methoxyphenyl)acrylamide 164N-(3-((5-chloro-4-((4-(dimethylphosphoryl)pyridin-3- 473.1 D A A D C Dyl)amino)pyrimidin-2-yl)amino)-4- methoxyphenyl)acrylamide 165N-(2-(3-(azepan-1-yl)prop-1-yn-1-yl)-5-((5-chloro-4-((2- 607.2 A A A D AA (dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide 166 N-(5-((5-chloro-4-((2- 581.2 AA A D A A (dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(3-(isopropyl(methyl)amino)prop-1-yn-1-yl)-4-methoxyphenyl)acrylamide 167 N-(5-((5-chloro-4-((2- 593.2 A A A A A A(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-(3-(piperidin-1-yl)prop-1-yn-1-yl)phenyl)acrylamide 168 N-(5-((5-chloro-4-((2- 607.2 A A A A A A(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(3-(cyclopentyl(methyl)amino)prop-1-yn-1-yl)-4-methoxyphenyl)acrylamide 176 N-(5-((5-chloro-4-((2- 607.2 A A A D(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)methyl)-4-methoxy-2-(3-(4-methylpiperidin-1-yl)prop-1-yn-1-yl)phenyl)acrylamide 177N-(2-(3-(ferf-butyl(methyl)amino)prop-1-yn-1-yl)-5- 595.2 A A A D((5-chloro-4-((2- (dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)methyl)-4-methoxyphenyl)acrylamide 178 N-(5-((5-chloro-4-((2- 622.2 BA A D (dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)methyl)-2-(3-(2-(dimethylamino)pyrrolidin-1-yl)prop-1-yn-1-yl)-4-methoxyphenyl)acrylamide 179 N-(5-((5-chloro-4-((2-607.2 (dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)methyl)-4-methoxy-2-(3-(2-methylpiperidin-1-yl)prop-1-yn-1-yl)phenyl)acrylamide 180 (Z)-N-(5-((5-chloro-4-((2- 555.2(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)methyl)-2-(3-(dimethylamino)prop-1-en-1-yl)-4-methoxyphenyl)acrylamide 181 (E)-N-(5-((5-chloro-4-((2- 555.2(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)methyl)-2-(3-(dimethylamino)prop-1-en-1-yl)-4-methoxyphenyl)acrylamide 182 N-(5-((5-chloro-4-((2- 611.2(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)methyl)-2-(3-(4-fluoropiperidin-1-yl)prop-1-yn-1-yl)-4-methoxyphenyl)acrylamide 183 N-(5-((5-chloro-4-((2- 623.2(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)methyl)-4-methoxy-2-(3-(methyl(tetrahydro-2H-pyran-4-yl)amino)prop-1-yn-1-yl)phenyl)acrylamide 184N-(5-((5-chloro-4-((2- 565.2(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)methyl)-2-(3-(dimethylamino)prop-1-yn-1-yl)-4-methoxyphenyl)but-2-ynamide 185N-(3-((5-chloro-2-(2-methoxy-4-(1-methyl-4-oxido- 528.11,4-azaphosphinan-4-yl)benzyl)pyrimidin-4- yl)oxy)phenyl)acrylamide ¹A =<50 nM; B = 50 → 100 nM; C = 101 nM → <250 nM; D = ≧250 nM

OTHER EMBODIMENTS

All publications, patents, and patent applications mentioned in thisspecification are herein incorporated by reference to the same extent asif each independent publication or patent application was specificallyand individually indicated to be incorporated by reference.

While the invention has been described in connection with specificembodiments thereof, it will be understood that it is capable of furthermodifications and this application is intended to cover any variations,uses, or adaptations of the invention following, in general, theprinciples of the invention and including such departures from thepresent disclosure that come within known or customary practice withinthe art to which the invention pertains and may be applied to theessential features hereinbefore set forth, and follows in the scope ofthe claims.

Other embodiments are within the claims.

1. A compound of the Formula:

or a pharmaceutically acceptable salt thereof, wherein U¹ and U² areboth N and U³ is C—R^(e); or U³ is N, one of U¹ and U² is N, and theother is C—R^(d); or U³ is C—R^(e), one of U¹ and U² is N, and the otheris C—R^(d); V¹ is O, S, NR^(V), CO, CH₂, or CF₂; R^(V) is H, alkyl,alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, or aryl; R^(d)is H, halo, CN, alkyl, cycloalkyl, alkoxy, haloalkyl, alkenyl,haloalkenyl or halocycloalkyl; R^(e) is H or NH₂; or, R^(d) and R^(e),together with the ring atom to which each is attached, form a 5- or6-membered ring containing one, two or three heteroatoms, independentlyselected from N, S and O, wherein the 5- or 6-membered ring so formed isindependently substituted by R^(h); R^(h) is H, C₁₋₄ alkyl, or halo;R^(g) is H, F, —P(O)(R^(3A))(R^(3B)), —S(O)N(R^(3C))(R^(3D)),—S(O)₂R^(3E), —C(O)N(R^(3F))(R^(3G)), —OC(O)N(R^(3F))(R^(3G)),—NR^(3H)C(O)OR^(3I), a 5- or 6-membered heterocyclic ring comprising 1,2, 3 or 4 N atoms; each R^(3A), R^(3B), R^(3C), R^(3D), R^(3E), R^(3F),R^(3G), R^(3H), and R^(3I) is, independently, selected from H, alkyl,alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, andheteroalkyl, or R^(3A) and R^(3B), or R^(3C) and R^(3D), or R^(3F) andR^(3G), together with the atom to which each is attached, form anoptionally substituted 5- or 6-membered heterocyclic ring; R^(g2) is H,F, W¹, —P(O)(R^(3A))(R^(3B)), —S(O)N(R^(3C))(R^(3D)), —S(O)₂R^(3E),—C(O)N(R^(3F))(R^(3G)), —OC(O)N(R^(3F))(R^(3G)), —NR^(3H)C(O)OR^(3I),C₁₋₆ alkoxy, C₁₋₄ alkyl, or, R^(g2) and R^(g) together with the atom towhich each is attached form an optionally substituted 5- to 7-memberedheterocyclic ring comprising 1-3 heteroatoms independently selected fromP, N, O and S; R^(g1) is H, F, —OR², —P(O)(R^(3A))(R^(3B)),—S(O)N(R^(3C))(R^(3D)), —S(O)₂R^(3E), —C(O)N(R^(3F))(R^(3G)),—OC(O)N(R^(3F))(R^(3G)), —NR^(3H)C(O)OR^(3I), or an optionallysubstituted 5- or 6-membered heterocyclic ring; Ring A is:

R^(b2) is H, F, or an optionally substituted 5- or 6-memberedheterocyclic ring containing 1, 2 or 3 N or O atoms; R^(b4) is H, F, W¹,C₁₋₆ alkoxy, C₃₋₆ alkenyloxy, C₃₋₆ cycloalkoxy, —OC(O)N(R^(5A))(R^(5B)),—NR^(5C)C(O)OR^(5D), or an optionally substituted 5- or 6-memberedheterocyclic ring comprising 1, 2 or 3 N or O atoms; each R^(5A),R^(5B), R^(5C), and R^(5D) is independently selected from H, alkyl,alkenyl, alkynyl, and heteroalkyl, or R^(5A) and R^(5B), together withthe atom to which each is attached, form an optionally substituted 5- or6-membered heterocyclic ring; R^(a1) is H, halo, W¹, —CN, —NO₂, —R¹,—OR², —O—NR¹R², —NR¹R², —NR¹—NR¹R², —NR¹—OR², —C(O)YR², —OC(O)YR²,—NR¹C(O)YR², —SC(O)YR², —NR¹C(═S)YR², —OC(═S)YR², —C(═S)YR²,—YC(═NR¹)YR², —YC(═N—OR¹)YR², —YC(═N—NR¹R²)YR², —YP(═O)(YR¹)(YR²),—S(O)_(r)R², —SO₂NR¹R², —NR¹SO₂NR¹R², or

X₁ and X₂ are each independently CH or N; or R^(a1) and R^(b4), togetherwith the atom to which each is attached, form an optionally substituted5- or 6-membered heterocyclic ring comprising 1, 2 or 3 heteroatomsindependently selected from N and O; R^(a2) is H, halo, C₁₋₆ alkyl, C₂₋₆alkenyl, C₃₋₆ cycloalkyl, C₁₋₆ alkoxy, C₂-6 alkenyloxy, C₃₋₆cycloalkyloxy or 4- to 7-membered heterocyclyl, wherein the alkyl,alkenyl, cycloalkyl, alkoxy, C₂-6 alkenyloxy, cycloalkyloxy andheterocyclyl are optionally substituted with one or more halo, amino,C₁₋₆ alkylamino, or di-C₁₋₆ alkylamino groups; Y is independently abond, —O—, —S— or —NR¹—; R¹ and R² are independently H or R¹⁵; R⁴ isalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl,heteroalkyl, heterocyclic and heteroaryl; W¹ is —NR⁷C(O)C(R¹¹)═CR⁹R¹⁰,—C(O)C(R¹¹)═CR⁹R¹⁰, —CH₂P(O)C(R¹¹)═CR⁹R¹⁰, —OP(O)C(R8)=CR9R10,—NR⁷S(O)₂C(R⁹)(R¹⁰)(R^(X)), —NR⁷S(O)₂C(R¹¹)═CR⁹R¹⁰, —NR⁷C(O)C≡C—R¹⁴,—NR⁷C(O)C(R⁹)(R¹⁰)(R^(X)),

R^(X) is halo; R⁷ is H, alkyl or heteroalkyl, wherein the alkyl andheteroalkyl groups are independently optionally substituted with anamino, alkylamino or dialkylamino group; R⁸ is C₁₋₆ alkyl; R⁹ and R¹⁰are independently H, halo, —C(O)R¹⁶, alkyl, alkoxy, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroalkyl, heterocyclylor heteroaryl, wherein R⁹ and R¹⁰, if not H, are optionally substitutedwith one or more halo, amino, alkylamino, dialkylamino, alkoxy,cycloalkyl, heterocyclyl or heteroaryl groups, wherein said group, ifnot halo, is optionally substituted with one or more halo, C₁₋₄ alkyl,alkoxyl, halo(C₁₋₄)alkyl or C₃₋₇ cycloalkyl groups; R¹¹ is H, halo,—C(O)—OR¹², alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,cycloalkynyl, aryl, heteroalkyl, heterocyclic, or heteroaryl, whereinR¹¹, if not H, is optionally substituted with one or more halo, amino,alkoxyl, cycloalkyl, heterocyclic or heteroaryl groups, wherein saidgroup, if not halo, is optionally substituted with one or more halo oralkyl, alkoxyl, cycloalkyl or heterocyclyl groups, wherein the alkyl,alkoxyl, cycloalkyl and heterocyclyl group is optionally substitutedwith one or more alkyl, halo or hydroxyl substituents; or R⁹ and R¹¹,taken together with the atom to which each is attached, form acycloalkenyl or heterocyclic ring; R¹² is alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroalkyl, heterocyclic,or heteroaryl; R¹³ is H or C₁₋₄ alkyl; R¹⁴ is R^(T) or R^(W); R¹⁵ isalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl,heteroalkyl, 4- to 7-membered heterocyclyl, or heteroaryl, wherein eachR¹⁵ is optionally substituted with one or more halo, cycloalkyl,heterocyclic or heteroaryl groups, wherein said cycloalkyl, heterocyclicor heteroaryl groups(s) are independently optionally substituted withone or more halo, alkyl, haloalkyl, hydroxyalkyl, amino, dialkylamino orcycloalkyl groups; R¹⁶ is OH, —O-alkyl, cycloalkyl, heterocyclyl, —NH₂,—NH-alkyl, or —N-dialkyl wherein the alkyl, cycloalkyl or heterocyclylmoiety is optionally substituted with halo, amino, alkylamino,dialkylamino, alkyl or hydroxyl; R^(T) is H or —CH₃; R^(W) is halo;substituted methyl; or an optionally substituted group selected from(C₂₋₆)alkyl, (C₁₋₆)heteroalkyl, heterocyclyl, aryl and heteroaryl;wherein the substituents on the optionally substituted (C₂₋₆)alkyl,(C₁₋₆)heteroalkyl, heterocyclyl, aryl and heteroaryl groups are selectedfrom halo, haloalkyl, alkoxy, heterocyclyl, substituted heterocyclyl,amino, alkylamino, and dialkylamino, and in the case of an optionallysubstituted heterocyclyl, the optional substituents may further beselected from hydroxyl, alkyl, haloalkyl, hyroxyalkyl, alkoxyalkyl,amino, alkylamino and dialkylamino; wherein (a) the compound is not oneof the following two compounds:

(b) at least one of R^(a1), R^(g2), and R^(b4) is W¹; (c) the compoundcomprises at least one —P(O)(R^(3A))(R^(3B)); and (d) the compoundfurther has one or more of the following features: R^(d) ishalo(C₃₋₅)cycloalkyl; R^(a2) is halo; substituted alkyl, substitutedalkoxy, or optionally substituted cycloalkyl, wherein substituents onthe alkyl, alkoxy or cycloalkyl groups are selected from halo, amino anddialkylamino groups; R^(a1) is an optionally substituted 4-memberedheterocycle; R^(a1) is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenylor heteroalkyl, and is substituted with one or more groups selected fromhalo, OH, heterocyclyl, substituted heterocyclyl, heteroaryl, andsubstituted heteroaryl; R^(a1) is heterocyclyl or heterocyclyl-O—,wherein R^(a1) is substituted with one or more groups selected from —OH,halo, 4-membered heterocyclyl, substituted 4-membered heterocyclyl andR¹⁸, wherein R¹⁸ is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl orheteroalkyl, and R¹⁸ is optionally substituted; R^(a1) and R^(b4),together with the atom to which each is attached, form an optionallysubstituted 5-membered heterocyclic ring; R^(a2) is an optionallysubstituted 4- to 7-membered membered heterocycle; R^(b4) is—NR⁷C(O)C(R¹¹)═CR⁹R¹⁰ or —NR⁷C(O)C C≡C—R^(W); R^(g1) is —OR²; R⁹or R¹⁰is cycloalkyl, —CO₂H, —CO₂-alkyl, —C(O)-heterocyclyl, —C(O)NH₂,—C(O)NH-alkyl or —C(O)N-dialkyl wherein an alkyl, cycloalkyl orheterocyclyl substituent or portion of a substituent is optionallysubstituted with amino, alkylamino, dialkylamino, alkyl or hydroxyl; oneor more of R⁹, R¹⁰ and R¹¹ is halo, haloalkyl, alkyl, alkoxy,heteroalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl,aryl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl orarylalkyl wherein alkyl, heterocylic, heteroaryl or aryl substituent, oran alkyl, heterocylic, heteroaryl or aryl portion of a substituent, isoptionally substituted with one or more groups selected from halo,haloalkyl, hydroxyl, hydroxyalkyl, amino, alkylamino, dialkylamino,alkyl, alkenyl, SO₂alkyl, oxo, heterocyclyl and heterocycle substitutedwith one or more alkyl, amino alkylamino, dialkylamino, hydroxyl,hydroxyalkyl, SO₂alkyl substituents; and, R⁹ and R¹¹, taken togetherwith the atom to which each is attached, form a cycloalkenyl orheterocyclic ring.
 2. The compound of claim 1 or a pharmaceuticallyacceptable salt thereof wherein: R^(d) is H, halo, CN, alkyl, alkoxy,haloalkyl, alkenyl, haloalkenyl or halocycloalkyl; W¹ is—NR⁷C(O)C(R¹¹)═CR⁹R¹⁰, —C(O)C(R¹¹)═CR⁹R¹⁰, —CH₂P(O)C(R¹¹)═CR⁹R¹⁰,—OP(O)(R⁸)═CR⁹R¹⁰, —NR⁷S(O)₂C(R¹¹)═CR⁹R¹⁰, —NR⁷C(O)C C≡C—R¹⁴,

R^(g) is H, —P(O)(R^(3A))(R^(3B)), —S(O)N(R^(3C))(R^(3D)), —S(O)₂R^(3E),—C(O)N(R^(3F))(R^(3G)), —OC(O)N(R^(3F))(R^(3G)), —NR^(3H)C(O)OR^(3I), a5- or 6-membered heterocyclic ring comprising 1, 2, 3 or 4 N atoms,wherein each of R^(3A), R^(3B), R^(3C), R^(3D), R^(3E), R^(3F), R^(3G),R^(3H), and R^(3I) is, independently, selected from H, alkyl, alkenyl,alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, and heteroalkyl, orR^(3A) and R^(3B), or R^(3C) and R^(3D), or R^(3F) and R^(3G), togetherwith the atoms to which each is attached, form an optionally substituted5- or 6-membered heterocyclic ring; and, R^(g1) is H, F,—P(O)(R^(3A))(R^(3B)), —S(O)N(R^(3C))(R^(3D)), —S(O)₂R^(3E),—C(O)N(R^(3F))(R^(3G)), —OC(O)N(R^(3F))(R^(3G)), —NR^(3H)C(O)OR^(3I), oran optionally substituted 5- or 6-membered heterocyclic ring; whereinthe variable terms are as defined in claim
 1. 3. The compound of claim1, 2 or 3, wherein said compound is described by any of Formulas(IIIa)-(IIIe), or a pharmaceutically acceptable salt thereof:

wherein R^(a1); R^(a2); R^(b2); R^(b4); R^(g); R^(g1); R^(g2); R^(d);and R^(h) are as defined in claim
 1. 4. The compound of claim 1, 2 or 3,wherein said compound is described by any of Formulas (IVa)-(IVe), or apharmaceutically acceptable salt thereof:

wherein R^(a2); R^(b2); R^(b4); R^(g); R^(g1); R^(g2); R^(d); and R^(h)are as defined in claim
 1. 5. The compound of claim 1, 2 or 3, whereinsaid compound is described by any of Formulas (Va)-(Ve), or apharmaceutically acceptable salt thereof:

wherein R^(a1); R^(a2); R^(b2); R^(b4); R^(g); R^(g1); R^(g2); R^(d);and R^(h) are as defined in claim
 1. 6. The compound of claim 1, 2 or 3,wherein said compound is described by any of Formulas (VIa)-(VIe), or apharmaceutically acceptable salt thereof:

wherein R^(a2); R^(b2); R^(b4); R^(g); R^(g1); R^(g2); R^(d); and R^(h)are as defined in claim 1, and R^(a1) is selected from W¹, —R¹,—C(O)YR², —C(═S)YR², —C(═NR¹)YR², —C(═N—OR¹)YR², —C(═N—NR¹R²)YR²,—S(O)_(r)R², and

each Y is, independently, a bond, —O—, —S— or —NR¹—; each occurrence ofR¹ and R² is, independently, selected from H, alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroalkyl, heterocyclicand heteroaryl; each of X₁ and X₂ is, independently, selected from CHand N; W¹ is as defined in claim 1; and R⁴ is selected from alkyl,alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl,heteroalkyl, heterocyclic and heteroaryl.
 7. The compound of claim 1, 2or 3, wherein said compound is described by any of Formulas(VIIa)-(VIIe), or a pharmaceutically acceptable salt thereof:

wherein R^(a1); R^(a2); R^(b4); R^(g); R^(g1); R^(g2); R^(d); and R^(h)are as defined in claim
 1. 8. The compound of claim 1, 2 or 3, whereinsaid compound is described by any of Formulas (VIIIa)-(VIIIe), or apharmaceutically acceptable salt thereof:

wherein R^(a2); R^(b2); R^(g); R^(g1); R^(g2); R^(d); and R^(h) are asdefined in claim 1, R^(a1) is selected from W¹, —R¹, —C(O)YR²,—C(═S)YR², —C(═NR¹)YR², —C(═N—OR¹)YR², —C(═N—NR¹R²)YR², —S(O)_(r)R², and

each Y is, independently, a bond, —O—, —S— or —NR¹—; W¹ is as defined inclaim 1; each occurrence of R¹ and R² is, independently, selected fromH, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl,aryl, heteroalkyl, heterocyclic and heteroaryl; each of X₁ and X₂ is,independently, selected from CH and N; and R⁴ is selected from alkyl,alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl,heteroalkyl, heterocyclic and heteroaryl.
 9. The compound of claim 1, 2or 3, wherein said compound is described by any of Formulas (IXa)-(IXe),or a pharmaceutically acceptable salt thereof:

wherein R^(a1) is W¹, —R¹, —C(O)YR², —C(═S)YR², —C(═NR¹)YR²,—C(═N—OR¹)YR², —C(═N—NR¹R²)YR², —S(O)_(r)R², or

each Y is, independently, a bond, —O—, —S— or —NR¹—; R^(b2); R^(b4);R^(g); R^(g1); R^(g2); R^(d); R^(h) and W¹ are as defined in claim 1;each occurrence of R¹ and R² is, independently, selected from H, alkyl,alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl,heteroalkyl, heterocyclic and heteroaryl; each of X₁ and X₂ is,independently, CH or N; and R⁴ is alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, cycloalkynyl, aryl, heteroalkyl, heterocyclic orheteroaryl.
 10. The compound of claim 1, 2 or 3, wherein said compoundis described by any of Formulas (Xa)-(Xe), or a pharmaceuticallyacceptable salt thereof:

wherein R^(b2); R^(b4); R^(g); R^(g1); R^(g2); R^(d); and R^(h) are asdefined in claim 1, R^(a1) is selected from W¹, —R¹, —C(O)YR²,—C(═S)YR², —C(═NR¹)YR², —C(═N—OR¹)YR², —C(═N—NR¹R²)YR², —S(O)_(r)R², and

each Y is, independently, a bond, —O—, —S— or —NR¹—; W¹ is as defined inclaim 1; each occurrence of R¹ and R² is, independently, selected fromH, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl,aryl, heteroalkyl, heterocyclic and heteroaryl; each of X₁ and X₂ is,independently, selected from CH and N; and R⁴ is selected from alkyl,alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl,heteroalkyl, heterocyclic and heteroaryl.
 11. The compound of any ofclaims 1-10, or a pharmaceutically acceptable salt thereof, whereinR^(a2) is H, halo, —CH₃, —CF₃, —CH₂CH₃, —OCH₃, —OCF₃, —OCH₂CH₃,—OCH₂CH₂N(CH₃)₂ or —O-heterocyclyl.
 12. The compound of any of claims1-10, or a pharmaceutically acceptable salt thereof, wherein R^(d) is H,Cl, F, Br, I, CN, CH₃, CF₃, —CH₂CH═CH₂, or cyclopropyl.
 13. The compoundof any of claims 1-6 or 8-10, or a pharmaceutically acceptable saltthereof, wherein R^(b2) is H.
 14. The compound of any of claims 1-10, ora pharmaceutically acceptable salt thereof, wherein R^(g1) is H,—P(O)(R^(3A))(R^(3B)) or —OR² and R^(g2) is H, F, C₁₋₆ alkyl, or C₁₋₆alkoxy, wherein R^(3A), R^(3B), and R² are as defined in claim
 1. 15.The compound of any of claims 1-10, or a pharmaceutically acceptablesalt thereof, wherein R^(g) is —P(O)(R^(3A))(R^(3B)), wherein R^(3A) andR^(3B), are as defined in claim
 1. 16. The compound of claim 15, or apharmaceutically acceptable salt thereof, wherein R^(g) is —P(O)(CH₃)₂or —P(O)(CH₂CH₃)₂.
 17. The compound of any of claims 1-10, or apharmaceutically acceptable salt thereof, wherein R^(g) is—S(O)₂R^(3E)), wherein R^(3E) is as defined in claim
 1. 18. The compoundof claim 17, or a pharmaceutically acceptable salt thereof, whereinR^(g) is —S(O)₂CH(CH₃)₂.
 19. The compound of any of claims 1-4 or 6-10,or a pharmaceutically acceptable salt thereof, wherein R^(a1) is a 4-,5-, 6- or 7-membered heterocycle which is optionally substituted withone or more groups selected from halo and R¹⁷, wherein R¹⁷ is an alkyl,cycloalkyl, heteroalkyl, 4- to 7-membered heterocyclyl or heteroarylgroup, wherein R¹⁷ is optionally substituted with one or more halo,alkyl, cycloalkyl, heterocyclic or heteroaryl groups, of which, saidcycloalkyl, heterocyclic or heteroaryl substituent is optionallysubstituted with one or more halo, alkyl, haloalkyl, hydroxyalkyl,amino, dialkylamino or cycloalkyl groups.
 20. The compound of claim 19,or a pharmaceutically acceptable salt thereof, wherein R^(a1) isselected from the following:


21. The compound of any of claims 1-3 or 5-10, or a pharmaceuticallyacceptable salt thereof, wherein R^(a1) is —OR², as defined in claim 1.22. The compound of claim 21, or a pharmaceutically acceptable saltthereof, wherein R^(a1) is selected from the following:


23. The compound of any of claims 1-3 or 5-10, or a pharmaceuticallyacceptable salt thereof, wherein R^(a1) is an optionally substitutedalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, orheteroalkyl group, wherein optional substituents are selected from halo,cycloalkyl, heterocyclic or heteroaryl groups, wherein said cycloalkyl,heterocyclic and heteroaryl substituent(s) are independently optionallysubstituted with one or more halo, alkyl, haloalkyl, hydroxyalkyl,amino, dialkylamino or cycloalkyl groups.
 24. The compound of claim 23,or a pharmaceutically acceptable salt thereof wherein R^(a1) is selectedfrom the following:


25. The compound of claim 23, or a pharmaceutically acceptable saltthereof wherein R^(a1) is of the Formula:

wherein: J¹ and J² are independently H, halo or R^(J); or J¹ and J²together with the atom to which each is attached form an optionallysubstituted ring which is C₃₋₈ cycloalkyl, 3- to 7-memberedheterocyclic, or heteroaryl; J³ and J⁴ are independently H or R^(J); orJ³ and J⁴ together with the atom to which each is attached form anoptionally substituted ring which is 3- to 7-membered heterocyclic orheteroaryl ring; R^(J) is C₁₋₆ alkyl, C₃₋₈ cycloalkyl, C₁₋₈ heteroalkyl,or 3- to 7-membered heterocyclyl, wherein each R^(J) is independentlyselected from halo, haloalkyl, hydroxyl, hydroxyalkyl, amino,alkylamino, dialkylamino, cycloalkyl, alkoxy, cycloalkoxy andheterocyclic groups, wherein the alkyl, cycloalkyl, and heterocyclicgroups on R^(J) are optionally substituted with one or more halo, alkyl,haloalkyl, hydroxyalkyl, alkoxyalkyl, amino, alkylamino, dialkylamino orcycloalkyl groups; and, z is 1-3.
 26. The compound of claim 25, or apharmaceutically acceptable salt thereof, wherein R^(a1) is selectedfrom the following:


27. The compound of any of claims 1-3 or 5-10, or a pharmaceuticallyacceptable salt thereof, wherein R^(b4) is —NR⁷C(O)C(R¹¹)═CR⁹R¹⁰,—NR⁷S(O)₂C(R⁹)(R¹⁰)(R^(X)), —NR⁷C(O)C≡C—R¹⁴, or—NR⁷C(O)C(R⁹)(R¹⁰)(R^(X)), wherein R⁷, R⁹, R¹⁰, R¹¹, R¹⁴, and R^(X) areas defined in claim
 1. 28. The compound of claim 27, or apharmaceutically acceptable salt thereof, wherein R^(b4) is—NHC(O)CH═CH₂ or is selected from the following:


29. The compound of claim 27, or a pharmaceutically acceptable saltthereof, wherein R^(b4) is —NHC(O)C≡CH or is selected from thefollowing:


30. The compound of any of claims 19-24, or a pharmaceuticallyacceptable salt thereof, wherein R^(b4) is W¹ as defined in claim
 1. 31.The compound of claim 30, wherein R^(a2) is R^(a2) is H, halo, —CH₃,—CF₃, —CH₂CH₃, —OCH₃, —OCF₃, —OCH₂CH₃, —OCH₂CH₂N(CH₃)₂ or—O-heterocyclyl.
 32. The compound of claim 30 or 31, or apharmaceutically acceptable salt thereof, wherein R^(g) is—P(O)(R^(3A))(R^(3B)), wherein R^(3A) and R^(3B), are as defined inclaim
 1. 33. The compound of claim 32, or a pharmaceutically acceptablesalt thereof, wherein R^(g) is —P(O)(CH₃)₂ or —P(O)(CH₂CH₃)₂.
 34. Thecompound of claim 30 or 31, or a pharmaceutically acceptable saltthereof, wherein R^(g) is —S(O)₂R^(3E)), wherein R^(3E) is as defined inclaim
 1. 35. The compound of claim 34, or a pharmaceutically acceptablesalt thereof, wherein R^(g) is —S(O)₂CH(CH₃)₂.
 36. The compound of anyof claims 32-35 wherein R^(d) is Cl, F, Br, I, or CH₃.
 37. The compoundof claim 1 or 2, wherein U¹ is N, U² is C—R^(d), and U³ is C—R^(e). 38.The compound of claim 1 or 2, wherein U¹ is C—R^(d), U² is N, and U³ isC—R^(e).
 33. The compound of claim 1 or 2, wherein U¹ is N, U² is N, andU³ is C—R^(e).
 39. The compound of claim 1 or 2, wherein U¹ is N; U² isC—R^(d); U³ is C—R^(e); R^(a2) is OCH₃; R^(g) or R^(g1) is—P(O)(R^(3A))(R^(3B)); each of R^(3A) and R^(3B) is, independently,selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,cycloalkynyl, and heteroalkyl, or R^(3A) and R^(3B), together with theatom to which each is attached, form a 5- or 6-membered heterocyclicring which is unsubstituted or substituted; R^(b4) is W¹ as defined inclaim
 1. 40. The compound of any of claims 30-39, wherein R^(d) is Cl.41. The compound of claim 1 or 2, wherein U³ is N, one of U¹ and U² isN, and the other is C—R^(d).
 42. A method for treating an EGFR-drivencancer in a subject, said method comprising administering to saidsubject a therapeutically effective amount of a compound of any ofclaims 1-41, or a pharmaceutically acceptable salt thereof.
 43. A methodfor treating an EGFR-driven cancer in a subject, said method comprising(a) providing a subject having an EGFR-driven cancer characterized bythe presence of a mutation in epidermal growth factor receptor kinase(EGFR), and (b) administering to said subject a therapeuticallyeffective amount of a compound of any of claims 1-41, or apharmaceutically acceptable salt thereof.
 44. The method of claim 43,wherein said EGFR-driven cancer is characterized by the presence of oneor more mutations selected from: (i) L858R, (ii) T790M, (iii) both L858Rand T790M, (iv) delE746_A750, and (v) both delE746_A750 and T790M. 45.The method of any of claims 42-44, wherein said EGFR-driven cancer is anon-small cell lung cancer (NSCLS); glioblastoma; pancreatic cancer;head and neck cancer (e.g., squamous cell carcinoma); breast cancer;colorectal cancer; epithelial cancer; ovarian cancer; prostate cancer;or an adenocarcinoma.
 46. The method of any of claims 42-45, furthercomprising administering to said subject a first kinase inhibitorselected from erlotinib, gefitinib, and pharmaceutically acceptablesalts thereof, within 6 days of administering said compound of any ofclaims 1-31, wherein each of said compound of any of claims 1-31 andsaid first kinase inhibitor are administered in an amount that togetheris sufficient to treat said EGFR-driven cancer.
 47. A method ofinhibiting the proliferation of a cell expressing an EGFR mutant, saidmethod comprising contacting said cell with a compound of any of claims1-31, or a pharmaceutically acceptable salt thereof, in an amountsufficient to inhibit said proliferation.
 48. The method of claim 47,wherein said EGFR mutant is characterized by the presence of one or moremutations in epidermal growth factor receptor kinase (EGFR) selectedfrom: (i) L858R, (ii) T790M, (iii) both L858R and T790M, (iv)delE746_A750, and (v) both delE746_A750 and T790M.
 49. The method ofclaims 47 or 48, wherein said cell is a cancer cell.
 50. The method ofclaim 49, wherein said cancer cell is a cell from a non-small cell lungcancer (NSCLS); glioblastoma; pancreatic cancer; head and neck cancer(e.g., squamous cell carcinoma); breast cancer; colorectal cancer;epithelial cancer; ovarian cancer; prostate cancer; or anadenocarcinoma.
 51. A method of treating an EGFR-driven cancerrefractory to a first kinase inhibitor selected from erlotinib,gefitinib, and pharmaceutically acceptable salts thereof, in a subject,said method comprising administering to said subject a compound of anyof claims 1-41, or a pharmaceutically acceptable salt thereof, in anamount sufficient to treat said cancer.
 52. A pharmaceutical compositioncomprising a compound of claim 1.